Key Points
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The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation
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Pharmacological inhibition of mTOR and selective gene targeting of mTORC1 or mTORC2 in podocytes and tubular epithelial cells has helped to elucidate their role in renal cell homeostasis, including in autophagy
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Mechanistic insights into the roles of mTOR complexes in regulating immune cell function are helping to improve understanding of the effects of mTOR inhibitors in renal disease and transplant rejection
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mTOR is increasingly recognized as having a fundamental role in the development of glomerular disease and in acute kidney injury; its role in fibrotic kidney disease is less certain
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New generation dual mTORC1 and mTORC2 inhibitors offer potential for the treatment of renal cell carcinoma
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mTOR inhibitors are associated with reduced rates of skin cancer and cytomegalovirus infection in renal transplant recipients
Abstract
The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation. Studies involving selective gene targeting of mTOR complexes (mTORC1 and mTORC2) in renal cell populations and/or pharmacologic mTOR inhibition have revealed important roles of mTOR in podocyte homeostasis and tubular transport. Important advances have also been made in understanding the role of mTOR in renal injury, polycystic kidney disease and glomerular diseases, including diabetic nephropathy. Novel insights into the roles of mTORC1 and mTORC2 in the regulation of immune cell homeostasis and function are helping to improve understanding of the complex effects of mTOR targeting on immune responses, including those that impact both de novo renal disease and renal allograft outcomes. Extensive experience in clinical renal transplantation has resulted in successful conversion of patients from calcineurin inhibitors to mTOR inhibitors at various times post-transplantation, with excellent long-term graft function. Widespread use of this practice has, however, been limited owing to mTOR-inhibitor- related toxicities. Unique attributes of mTOR inhibitors include reduced rates of squamous cell carcinoma and cytomegalovirus infection compared to other regimens. As understanding of the mechanisms by which mTORC1 and mTORC2 drive the pathogenesis of renal disease progresses, clinical studies of mTOR pathway targeting will enable testing of evolving hypotheses.
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References
Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo) 28, 721–726 (1975).
Calne, R. Y. et al. Rapamycin for immunosuppression in organ allografting. Lancet 2, 227 (1989).
Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).
Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15, 155–162 (2014).
Flinn, R. J., Yan, Y., Goswami, S., Parker, P. J. & Backer, J. M. The late endosome is essential for mTORC1 signaling. Mol. Biol. Cell 21, 833–841 (2010).
Kim, S. G. et al. Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol. Cell 49, 172–185 (2013).
Yadav, R. B. et al. mTOR direct interactions with Rheb-GTPase and raptor: sub-cellular localization using fluorescence lifetime imaging. BMC Cell Biol. 14, 3 (2013).
Fournier, M. J. et al. Inactivation of the mTORC1-eukaryotic translation initiation factor 4E pathway alters stress granule formation. Mol. Cell. Biol. 33, 2285–2301 (2013).
Guertin, D. A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11, 859–871 (2006).
Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).
Xie, J. & Proud, C. G. Crosstalk between mTOR complexes. Nat. Cell Biol. 15, 1263–1265 (2013).
Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015).
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
Gaubitz, C. et al. Molecular basis of the rapamycin insensitivity of target of rapamycin complex 2. Mol. Cell 58, 977–988 (2015).
Zeng, Z. et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509–3512 (2007).
Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).
Brunn, G. J. et al. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 15, 5256–5267 (1996).
Yu, K. et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 69, 6232–6240 (2009).
Bendell, J. C. et al. A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma. Cancer 121, 3481–3490 (2015).
Pavenstadt, H., Kriz, W. & Kretzler, M. Cell biology of the glomerular podocyte. Physiol. Rev. 83, 253–307 (2003).
Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).
Inoki, K. et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121, 2181–2196 (2011).
Groth, C. G. et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 67, 1036–1042 (1999).
Schwarz, C., Bohmig, G. A., Steininger, R., Mayer, G. & Oberbauer, R. Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression. Nephrol. Dial. Transplant. 16, 378–382 (2001).
da Silva, C. A. et al. Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression. Am. J. Physiol. Renal Physiol. 297, F916–F922 (2009).
Wu, M. S., Hung, C. C. & Chang, C. T. Renal calcium handling after rapamycin conversion in chronic allograft dysfunction. Transpl. Int. 19, 140–145 (2006).
Tataranni, T. et al. Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression. Am. J. Transplant. 11, 1656–1664 (2011).
Haller, M. et al. Sirolimus induced phosphaturia is not caused by inhibition of renal apical sodium phosphate cotransporters. PLoS ONE 7, e39229 (2012).
Kempe, D. S. et al. Rapamycin-induced phosphaturia. Nephrol. Dial. Transplant. 25, 2938–2944 (2010).
Gleixner, E. M. et al. V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis. Cell Rep. 8, 10–19 (2014).
Grahammer, F. et al. mTOR regulates endocytosis and nutrient transport in proximal tubular cells. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2015111224 (2016).
Grahammer, F. et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc. Natl Acad. Sci. USA 111, E2817–E2826 (2014).
Lang, F. & Pearce, D. Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway. Nephrol. Dial. Transplant. 31, 200–205 (2015).
Lu, M. et al. mTOR complex-2 activates ENaC by phosphorylating SGK1. J. Am. Soc. Nephrol. 21, 811–818 (2010).
Gleason, C. E. et al. mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. J. Clin. Invest. 125, 117–128 (2015).
Grahammer, F. et al. mTORC2 critically regulates renal potassium handling. J. Clin. Invest. 126, 1773–1782 (2016).
Canaud, G. et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N. Engl. J. Med. 371, 303–312 (2014).
Jindra, P. T., Jin, Y. P., Rozengurt, E. & Reed, E. F. HLA class I antibody-mediated endothelial cell proliferation via the mTOR pathway. J. Immunol. 180, 2357–2366 (2008).
Jindra, P. T., Jin, Y. P., Jacamo, R., Rozengurt, E. & Reed, E. F. MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway. Biochem. Biophys. Res. Commun. 369, 781–787 (2008).
de Sandes-Freitas, T. V. et al. Subclinical lesions and donor-specific antibodies in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen followed by early conversion to sirolimus. Transplantation 99, 2372–2381 (2015).
Liefeldt, L. et al. Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation. Am. J. Transplant. 12, 1192–1198 (2012).
Croze, L. E. et al. Conversion to mammalian target of rapamycin inhibitors increases risk of de novo donor-specific antibodies. Transpl. Int. 27, 775–783 (2014).
Lepin, E. J. et al. Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts. Am. J. Transplant. 6, 1560–1571 (2006).
Jindra, P. T. et al. Anti-MHC class I antibody activation of proliferation and survival signaling in murine cardiac allografts. J. Immunol. 180, 2214–2224 (2008).
Kim, Y. C. & Guan, K. L. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 125, 25–32 (2015).
Ganley, I. G. et al. ULK1. ATG13. FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284, 12297–12305 (2009).
Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).
Jung, C. H. et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).
Fougeray, S. & Pallet, N. Mechanisms and biological functions of autophagy in diseased and ageing kidneys. Nat. Rev. Nephrol. 11, 34–45 (2015).
Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010).
Kawakami, T. et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J. Am. Soc. Nephrol. 26, 1040–1052 (2015).
Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011).
Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).
Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).
Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).
Zhuo, L. et al. Expression and mechanism of mammalian target of rapamycin in age-related renal cell senescence and organ aging. Mech. Ageing Dev. 130, 700–708 (2009).
Zhang, S. et al. SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence. Mech. Ageing Dev. 133, 387–400 (2012).
Weichhart, T., Hengstschlager, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15, 599–614 (2015).
Fantus, D. & Thomson, A. W. Evolving perspectives of mTOR complexes in immunity and transplantation. Am. J. Transplant. 15, 891–902 (2015).
Lo, Y. C., Lee, C. F. & Powell, J. D. Insight into the role of mTOR and metabolism in T cells reveals new potential approaches to preventing graft rejection. Curr. Opin. Organ. Transplant 19, 363–371 (2014).
Turner, J. E., Paust, H. J., Steinmetz, O. M. & Panzer, U. The Th17 immune response in renal inflammation. Kidney Int. 77, 1070–1075 (2010).
Rogers, N. M., Ferenbach, D. A., Isenberg, J. S., Thomson, A. W. & Hughes, J. Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat. Rev. Nephrol. 10, 625–643 (2014).
Park, C. O. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).
Batal, I. et al. Dendritic cells in kidney transplant biopsy samples are associated with T cell infiltration and poor allograft survival. J. Am. Soc. Nephrol. 26, 3102–3113 (2015).
Turnquist, H. R. et al. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J. Immunol. 178, 7018–7031 (2007).
Hackstein, H. et al. Rapamycin inhibits IL-4—induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 101, 4457–4463 (2003).
Turnquist, H. R. et al. mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPS. Blood 115, 4758–4769 (2010).
Amiel, E. et al. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J. Immunol. 189, 2151–2158 (2012).
Brown, J., Wang, H., Suttles, J., Graves, D. T. & Martin, M. Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1. J. Biol. Chem. 286, 44295–44305 (2011).
Raich-Regue, D. et al. mTORC2 deficiency in myeloid dendritic cells enhances their allogeneic Th1 and Th17 stimulatory ability after TLR4 ligation in vitro and in vivo. J. Immunol. 194, 4767–4776 (2015).
Raich-Regue, D. et al. Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8C effector T cell responses. Oncoimmunology http://dx.doi.org/10.1080/2162402X.2016.1146841 (2016).
Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).
Lee, K. et al. Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J. Exp. Med. 209, 713–728 (2012).
Tian, L., Lu, L., Yuan, Z., Lamb, J. R. & Tam, P. K. Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery. Transplantation 77, 183–189 (2004).
Haxhinasto, S., Mathis, D. & Benoist, C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008).
Battaglia, M., Stabilini, A. & Roncarolo, M. G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005).
Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).
Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).
Ray, J. P. et al. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690–702 (2015).
Matz, M. et al. Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation. Transpl. Int. 25, 1106–1116 (2012).
Benhamron, S. & Tirosh, B. Direct activation of mTOR in B lymphocytes confers impairment in B-cell maturation andloss of marginal zone B cells. Eur. J. Immunol. 41, 2390–2396 (2011).
Lee, K. et al. Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood 122, 2369–2379 (2013).
Keating, R. et al. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat. Immunol. 14, 1266–1276 (2013).
Limon, J. J. et al. mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition. Proc. Natl Acad. Sci. USA 111, E5076–E5085 (2014).
Jin, Y. P., Valenzuela, N. M., Ziegler, M. E., Rozengurt, E. & Reed, E. F. Everolimus inhibits anti-HLA I antibody-mediated endothelial cell signaling, migration and proliferation more potently than sirolimus. Am. J. Transplant. 14, 806–819 (2014).
Marcais, A. et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat. Immunol. 15, 749–757 (2014).
Shin, B. H. et al. Regulation of anti-HLA antibody-dependent natural killer cell activation by immunosuppressive agents. Transplantation 97, 294–300 (2014).
Prevot, N. et al. Mammalian target of rapamycin complex 2 regulates invariant NKT cell development and function independent of promyelocytic leukemia zinc-finger. J. Immunol. 194, 223–230 (2015).
Ochiai, T. et al. Effects of rapamycin in experimental organ allografting. Transplantation 56, 15–19 (1993).
Stepkowski, S. M., Chen, H., Daloze, P. & Kahan, B. D. Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat. Transplantation 51, 22–26 (1991).
Poston, R. S. et al. Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation 100, 67–74 (1999).
Ikonen, T. S. et al. Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates. Transplantation 70, 969–975 (2000).
Nakamura, T., Nakao, T., Yoshimura, N. & Ashihara, E. Rapamycin prolongs cardiac allograft survival in a mouse model by inducing myeloid-derived suppressor cells. Am. J. Transplant. 15, 2364–2377 (2015).
Page, A. et al. CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model. Am. J. Transplant. 12, 115–125 (2012).
Pan, H. et al. The second-generation mTOR kinase inhibitor INK128 exhibits anti-inflammatory activity in lipopolysaccharide-activated RAW 264.7 cells. Inflammation 37, 756–765 (2014).
Rosborough, B. R. et al. Adenosine triphosphate-competitive mTOR inhibitors: a new class of immunosuppressive agents that inhibit allograft rejection. Am. J. Transplant. 14, 2173–2180 (2014).
Zhang, L. et al. Abrogation of chronic rejection in rat model system involves modulation of the mTORC1 and mTORC2 pathways. Transplantation 96, 782–790 (2013).
Murgia, M. G., Jordan, S. & Kahan, B. D. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int. 49, 209–216 (1996).
MacDonald, A. S. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 71, 271–280 (2001).
Kahan, B. D., Julian, B. A., Pescovitz, M. D., Vanrenterghem, Y. & Neylan, J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation 68, 1526–1532 (1999).
Kahan, B. D. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune, US Study Group. Lancet 356, 194–202 (2000).
Kreis, H. et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 69, 1252–1260 (2000).
Kreis, H. et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J. Am. Soc. Nephrol. 15, 809–817 (2004).
Ekberg, H. et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N. Engl. J. Med. 357, 2562–2575 (2007).
Flechner, S. M. et al. The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am. J. Transplant. 11, 1633–1644 (2011).
Webster, A. C., Lee, V. W., Chapman, J. R. & Craig, J. C. Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst. Rev., CD004290 (2006).
Lim, W. H. et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am. J. Transplant. 14, 2106–2119 (2014).
Su, L. et al. Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis. Int. Urol. Nephrol. 46, 2035–2044 (2014).
Murakami, N., Riella, L. V. & Funakoshi, T. Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis. Am. J. Transplant. 14, 2317–2327 (2014).
Mandelbrot, D. A. et al. Effect of ramipril on urinary protein excretion in maintenance renal transplant patients converted to sirolimus. Am. J. Transplant. 15, 3174–3184 (2015).
Lewkowicz, N. et al. Dysfunction of CD4+CD25high T regulatory cells in patients with recurrent aphthous stomatitis. J. Oral Pathol. Med. 37, 454–461 (2008).
Sabbatini, M. et al. Oscillatory mTOR inhibition and Treg increase in kidney transplantation. Clin. Exp. Immunol. 182, 230–240 (2015).
Morelon, E. et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 72, 787–790 (2001).
Joannides, R. et al. Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine. Am. J. Transplant. 11, 2414–2422 (2011).
Thierry, A. et al. Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation. Am. J. Transplant. 11, 2153–2161 (2011).
Heilman, R. L. et al. Results of a prospective randomized trial of sirolimus conversion in kidney transplant recipients on early corticosteroid withdrawal. Transplantation 92, 767–773 (2011).
Glotz, D. et al. Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids. Transplantation 89, 1511–1517 (2010).
Li, H. & Pauza, C. D. Rapamycin increases the yield and effector function of human γδ T cells stimulated in vitro. Cancer Immunol. Immunother. 60, 361–370 (2011).
Clippinger, A. J., Maguire, T. G. & Alwine, J. C. The changing role of mTOR kinase in the maintenance of protein synthesis during human cytomegalovirus infection. J. Virol. 85, 3930–3939 (2011).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Hirsch, H. H., Yakhontova, K., Lu, M. & Manzetti, J. BK polyomavirus replication in renal tubular epithelial cells is inhibited by sirolimus, but activated by tacrolimus through a pathway involving FKBP-12. Am. J. Transplant. 16, 821–832 (2015).
Ferrer, I. R. et al. Cutting edge: rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses. J. Immunol. 185, 2004–2008 (2010).
Nashan, B. et al. Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation 93, 1075–1085 (2012).
Tedesco-Silva, H. et al. Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am. J. Transplant. 15, 2655–2664 (2015).
Polanco, N. et al. Everolimus-based immunosuppression therapy for BK virus nephropathy. Transplant Proc. 47, 57–61 (2015).
Knoll, G. A. et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 349, g6679 (2014).
Diekmann, F. et al. Treatment with sirolimus is associated with less weight gain after kidney transplantation. Transplantation 96, 480–486 (2013).
Halleck, F. et al. An evaluation of sirolimus in renal transplantation. Expert Opin. Drug Metab. Toxicol. 8, 1337–1356 (2012).
Susantitaphong, P. et al. World incidence of AKI: a meta-analysis. Clin. J. Am. Soc. Nephrol. 8, 1482–1493 (2013).
Rimes-Stigare, C. et al. Evolution of chronic renal impairment and long-term mortality after de novo acute kidney injury in the critically ill; a Swedish multi-centre cohort study. Crit. Care 19, 221 (2015).
Himmelfarb, J. & Ikizler, T. A. Acute kidney injury: changing lexicography, definitions, and epidemiology. Kidney Int. 71, 971–976 (2007).
Smith, K. D. et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J. Am. Soc. Nephrol. 14, 1037–1045 (2003).
McTaggart, R. A. et al. Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am. J. Transplant. 3, 416–423 (2003).
Loverre, A. et al. Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. J. Am. Soc. Nephrol. 15, 2675–2686 (2004).
Goncalves, G. M. et al. The role of immunosuppressive drugs in aggravating renal ischemia and reperfusion injury. Transplant Proc. 39, 417–420 (2007).
Fuller, T. F. et al. Sirolimus delays recovery of rat kidney transplants after ischemia-reperfusion injury. Transplantation 76, 1594–1599 (2003).
Inman, S. R. et al. Rapamycin preserves renal function compared with cyclosporine A after ischemia/reperfusion injury. Urology 62, 750–754 (2003).
Cicora, F. et al. Sirolimus in kidney transplant donors and clinical and histologic improvement in recipients: rat model. Transplant. Proc. 42, 365–370 (2010).
Lieberthal, W. et al. Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. Am. J. Physiol. Renal Physiol. 281, F693–F706 (2001).
Lui, S. L. et al. Effect of rapamycin on renal ischemia-reperfusion injury in mice. Transpl. Int. 19, 834–839 (2006).
Yang, B. et al. Inflammation and caspase activation in long-term renal ischemia/reperfusion injury and immunosuppression in rats. Kidney Int. 68, 2050–2067 (2005).
Khan, S. et al. Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. J. Mol. Cell Cardiol. 41, 256–264 (2006).
Cicora, F. et al. Preconditioning donor with a combination of tacrolimus and rapamacyn to decrease ischaemia-reperfusion injury in a rat syngenic kidney transplantation model. Clin. Exp. Immunol. 167, 169–177 (2012).
Viklicky, O. et al. Effect of sirolimus on renal ischaemia/reperfusion injury in normotensive and hypertensive rats. Transpl. Int. 17, 432–441 (2004).
Goncalves, G. M. et al. The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury. Kidney Int. 70, 1742–1749 (2006).
Nakagawa, S., Nishihara, K., Inui, K. & Masuda, S. Involvement of autophagy in the pharmacological effects of the mTOR inhibitor everolimus in acute kidney injury. Eur. J. Pharmacol. 696, 143–154 (2012).
Kezic, A., Thaiss, F., Becker, J. U., Tsui, T. Y. & Bajcetic, M. Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury. Am. J. Nephrol. 37, 291–301 (2013).
Izzedine, H. et al. Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven. Ann. Oncol. 24, 2421–2425 (2013).
Rai, P. et al. mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN. Am. J. Physiol. Renal Physiol. 305, F343–354 (2013).
Axelsson, J., Rippe, A. & Rippe, B. Acute hyperglycemia induces rapid, reversible increases in glomerular permeability in nondiabetic rats. Am. J. Physiol. Renal Physiol. 298, F1306–F1312 (2010).
Kuwabara, A., Satoh, M., Tomita, N., Sasaki, T. & Kashihara, N. Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats. Diabetologia 53, 2056–2065 (2010).
McCarthy, E. T. et al. TNF-α increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J. Am. Soc. Nephrol. 9, 433–438 (1998).
Axelsson, J., Rippe, A., Oberg, C. M. & Rippe, B. Rapid, dynamic changes in glomerular permeability to macromolecules during systemic angiotensin II (ANG II) infusion in rats. Am. J. Physiol. Renal Physiol. 303, F790–F799 (2012).
Axelsson, J. Rippe, A. & Rippe, B. mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside. Am. J. Physiol. Renal Physiol. 308, F1056–F1064 (2015).
Stylianou, K. et al. Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice. Nephrol. Dial. Transplant. 27, 3141–3148 (2012).
DiJoseph, J. F., Sharma, R. N. & Chang, J. Y. The effect of rapamycin on kidney function in the Sprague-Dawley rat. Transplantation 53, 507–513 (1992).
Di Joseph, J. F. & Sehgal, S. N. Functional and histopathologic effects of rapamycin on mouse kidney. Immunopharmacol. Immunotoxicol. 15, 45–56 (1993).
Andoh, T. F., Burdmann, E. A., Fransechini, N., Houghton, D. C. & Bennett, W. M. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int. 50, 1110–1117 (1996).
DiJoseph, J. F., Mihatsch, M. J. & Sehgal, S. N. Renal effects of rapamycin in the spontaneously hypertensive rat. Transpl. Int. 7, 83–88 (1994).
Grahammer, F., Wanner, N. & Huber, T. B. mTOR controls kidney epithelia in health and disease. Nephrol. Dial. Transplant. 29 (Suppl. 1), i9–i18 (2014).
Mao, J. et al. Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation. Am. J. Physiol. Renal Physiol. 307, F1023–F1032 (2014).
Jeruschke, S. et al. Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling. PLoS ONE 8, e55980 (2013).
Letavernier, E. et al. Sirolimus interacts with pathways essential for podocyte integrity. Nephrol. Dial. Transplant. 24, 630–638 (2009).
Muller-Krebs, S. et al. Cellular effects of everolimus and sirolimus on podocytes. PLoS ONE 8, e80340 (2013).
Vollenbroker, B. et al. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes. Am. J. Physiol. Renal Physiol. 296, F418–F426 (2009).
Canaud, G. et al. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat. Med. 19, 1288–1296 (2013).
Narres, M. et al. The incidence of end-stage renal disease in the diabetic (compared to the non-diabetic) population: A systematic review. PLoS ONE 11, e0147329 (2016).
Ibrahim, H. N. & Hostetter, T. H. Diabetic nephropathy. J. Am. Soc. Nephrol. 8, 487–493 (1997).
Mori, H. et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem. Biophys. Res. Commun. 384, 471–475 (2009).
Chen, J. K., Chen, J., Thomas, G., Kozma, S. C. & Harris, R. C. S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy. Am. J. Physiol. Renal Physiol. 297, F585–F593 (2009).
Sakaguchi, M. et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem. Biophys. Res. Commun. 340, 296–301 (2006).
Yang, Y. et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am. J. Nephrol. 27, 495–502 (2007).
Lloberas, N. et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J. Am. Soc. Nephrol. 17, 1395–1404 (2006).
Eid, A. A. et al. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury. Diabetes 62, 2935–2947 (2013).
Stylianou, K. et al. The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin. Nephrol. Dial. Transplant. 26, 498–508 (2011).
Lui, S. L. et al. Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. Nephrol. Dial. Transplant. 23, 2768–2776 (2008).
Lui, S. L. et al. Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice. Lupus 17, 305–313 (2008).
Ramos-Barron, A. et al. Prevention of murine lupus disease in (NZBxNZW)F1 mice by sirolimus treatment. Lupus 16, 775–781 (2007).
Warner, L. M., Adams, L. M. & Sehgal, S. N. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Arthritis Rheum. 37, 289–297 (1994).
Yap, D. Y., Ma, M. K., Tang, C. S. & Chan, T. M. Proliferation signal inhibitors in the treatment of lupus nephritis: preliminary experience. Nephrol. (Carlton) 17, 676–680 (2012).
Fernandez, D., Bonilla, E., Mirza, N., Niland, B. & Perl, A. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2983–2988 (2006).
Greka, A. & Mundel, P. Cell biology and pathology of podocytes. Annu. Rev. Physiol. 74, 299–323 (2012).
Ito, N. et al. mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome. Lab Invest. 91, 1584–1595 (2011).
Lui, S. L. et al. Rapamycin attenuates the severity of murine adriamycin nephropathy. Am. J. Nephrol. 29, 342–352 (2009).
Ramadan, R. et al. Early treatment with everolimus exerts nephroprotective effect in rats with adriamycin-induced nephrotic syndrome. Nephrol. Dial. Transplant. 27, 2231–2241 (2012).
Keller, K. et al. Everolimus inhibits glomerular endothelial cell proliferation and VEGF, but not long-term recovery in experimental thrombotic microangiopathy. Nephrol. Dial. Transplant. 21, 2724–2735 (2006).
Bagchus, W. M., Hoedemaeker, P. J., Rozing, J. & Bakker, W. W. Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. A sequential histological and ultrastructural study in the rat. Lab Invest. 55, 680–687 (1986).
Wittmann, S. et al. The mTOR inhibitor everolimus attenuates the time course of chronic anti-Thy1 nephritis in the rat. Nephron Exp. Nephrol. 108, e45–e56 (2008).
Daniel, C., Ziswiler, R., Frey, B., Pfister, M. & Marti, H. P. Proinflammatory effects in experimental mesangial proliferative glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin derivative. Exp. Nephrol. 8, 52–62 (2000).
Daniel, C. et al. Mechanisms of everolimus-induced glomerulosclerosis after glomerular injury in the rat. Am. J. Transplant. 5, 2849–2861 (2005).
Vogelbacher, R., Wittmann, S., Braun, A., Daniel, C. & Hugo, C. The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation 84, 1492–1499 (2007).
Tian, J., Wang, Y., Liu, X., Zhou, X. & Li, R. Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. Exp. Biol. Med. (Maywood) 240, 936–945 (2015).
Heymann, W., Hackel, D. B., Harwood, S., Wilson, S. G. & Hunter, J. L. Production of nephrotic syndrome in rats by Freund's adjuvants and rat kidney suspensions. Proc. Soc. Exp. Biol. Med. 100, 660–664 (1959).
Farquhar, M. G., Saito, A., Kerjaschki, D. & Orlando, R. A. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J. Am. Soc. Nephrol. 6, 35–47 (1995).
Naumovic, R. et al. Effects of rapamycin on active Heymann nephritis. Am. J. Nephrol. 27, 379–389 (2007).
Stratakis, S. et al. Rapamycin ameliorates proteinuria and restores nephrin and podocin expression in experimental membranous nephropathy. Clin. Dev. Immunol. 941, 93 (2013).
Kurayama, R. et al. Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis. Lab Invest. 91, 992–1006 (2011).
Hochegger, K. et al. Differential effects of rapamycin in anti-GBM glomerulonephritis. J. Am. Soc. Nephrol. 19, 1520–1529 (2008).
Kirsch, A. H. et al. The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response. Am. J. Physiol. Renal Physiol. 303, F569–F575 (2012).
Cruzado, J. M. et al. Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy. Nephrol. Dial. Transplant. 26, 3596–3602 (2011).
Tumlin, J. A. et al. A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 1, 109–116 (2006).
Cho, M. E., Hurley, J. K. & Kopp, J. B. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am. J. Kidney Dis. 49, 310–317 (2007).
Letavernier, E. et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin. J. Am. Soc. Nephrol. 2, 326–333 (2007).
Patel, P., Pal, S., Ashley, C., Sweny, P. & Burns, A. Combination therapy with sirolimus (rapamycin) and tacrolimus (FK-506) in treatment of refractory minimal change nephropathy, a clinical case report. Nephrol. Dial. Transplant. 20, 985–987 (2005).
Ong, A. C., Devuyst, O., Knebelmann, B. & Walz, G. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet 385, 1993–2002 (2015).
Grantham, J. J. Clinical practice. Autosomal dominant polycystic kidney disease. N. Engl. J. Med. 359, 1477–1485 (2008).
Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med. 364, 1533–1543 (2011).
Torres, V. E. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407–2418 (2012).
Tao, Y., Kim, J., Schrier, R. W. & Edelstein, C. L. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J. Am. Soc. Nephrol. 16, 46–51 (2005).
Shillingford, J. M. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl Acad. Sci. USA 103, 5466–5471 (2006).
Renken, C., Fischer, D. C., Kundt, G., Gretz, N. & Haffner, D. Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrol. Dial. Transplant. 26, 92–100 (2011).
Belibi, F., Ravichandran, K., Zafar, I., He, Z. & Edelstein, C. L. mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease. Am. J. Physiol. Renal Physiol. 300, F236–F244 (2011).
Distefano, G. et al. Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Mol. Cell. Biol. 29, 2359–2371 (2009).
Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 12, 1115–1122 (2010).
Boletta, A. Emerging evidence of a link between the polycystins and the mTOR pathways. Pathog. 2, 6 (2009).
Takiar, V. et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl Acad. Sci. USA 108, 2462–2467 (2011).
Huber, T. B., Walz, G. & Kuehn, E. W. mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression. Kidney Int. 79, 502–511 (2011).
Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).
Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).
Grantham, J. J., Bennett, W. M. & Perrone, R. D. mTOR inhibitors and autosomal dominant polycystic kidney disease. N. Engl. J. Med. 364, 286–287 (2011).
Levey, A. S. & Stevens, L. A. mTOR inhibitors and autosomal dominant polycystic kidney disease. N. Engl. J. Med. 364, 287 (2011).
Novalic, Z. et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J. Am. Soc. Nephrol. 23, 842–853 (2012).
Perico, N. et al. Sirolimus therapy to halt the progression of ADPKD. J. Am. Soc. Nephrol. 21, 1031–1040 (2010).
Riegersperger, M., Herkner, H. & Sunder-Plassmann, G. Pulsed oral sirolimus in advanced autosomal-dominant polycystic kidney disease (Vienna RAP Study): study protocol for a randomized controlled trial. Trials 16, 182 (2015).
Braun, W. E., Schold, J. D., Stephany, B. R., Spirko, R. A. & Herts, B. R. Low-dose rapamycin (sirolimus) effects in autosomal dominant polycystic kidney disease: an open-label randomized controlled pilot study. Clin. J. Am. Soc. Nephrol. 9, 881–888 (2014).
Ravichandran, K. et al. An mTOR anti-sense oligonucleotide decreases polycystic kidney disease in mice with a targeted mutation in Pkd2. Hum. Mol. Genet. 23, 4919–4931 (2014).
Jain, S., Bicknell, G. R., Whiting, P. H. & Nicholson, M. L. Rapamycin reduces expression of fibrosis-associated genes in an experimental model of renal ischaemia reperfusion injury. Transplant Proc. 33, 556–558 (2001).
Jolicoeur, E. M. et al. Combination therapy of mycophenolate mofetil and rapamycin in prevention of chronic renal allograft rejection in the rat. Transplantation 75, 54–59 (2003).
Rangan, G. K. & Coombes, J. D. Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis. Nephrol. Dial. Transplant. 22, 2175–2182 (2007).
Wu, M. J. et al. Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int. 69, 2029–2036 (2006).
Bonegio, R. G. et al. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. J. Am. Soc. Nephrol. 16, 2063–2072 (2005).
Kramer, S. et al. Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. Am. J. Physiol. Renal Physiol. 294, F440–F449 (2008).
Li, J. et al. Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis. Kidney Int. 88, 515–527 (2015).
Grahammer, F. Halting renal fibrosis: an unexpected role for mTORC2 signaling. Kidney Int. 88, 437–439 (2015).
Chen, G. et al. Rapamycin ameliorates kidney fibrosis by inhibiting the activation of mTOR signaling in interstitial macrophages and myofibroblasts. PLoS ONE 7, e33626 (2012).
Rahimi, R. A. et al. Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-β. Cancer Res. 69, 84–93 (2009).
Jiang, L. et al. Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. J. Am. Soc. Nephrol. 24, 1114–1126 (2013).
Dey, N., Ghosh-Choudhury, N., Kasinath, B. S. & Choudhury, G. G. TGFβ-stimulated microRNA-21 utilizes PTEN to orchestrate AKT/mTORC1 signaling for mesangial cell hypertrophy and matrix expansion. PLoS ONE 7, e42316 (2012).
Koch, M., Mengel, M., Poehnert, D. & Nashan, B. Effects of everolimus on cellular and humoral immune processes leading to chronic allograft nephropathy in a rat model with sensitized recipients. Transplantation 83, 498–505 (2007).
Viklicky, O. et al. SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation 69, 497–502 (2000).
Lutz, J., Zou, H., Liu, S., Antus, B. & Heemann, U. Apoptosis and treatment of chronic allograft nephropathy with everolimus. Transplantation 76, 508–515 (2003).
Luo, L., Sun, Z. & Luo, G. Rapamycin is less fibrogenic than Cyclosporin A as demonstrated in a rat model of chronic allograft nephropathy. J. Surg. Res. 179, e255–263 (2013).
Liu, Q. et al. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res. 73, 2574–2586 (2013).
Palin, N. K., Savikko, J. & Koskinen, P. K. Sirolimus inhibits lymphangiogenesis in rat renal allografts, a novel mechanism to prevent chronic kidney allograft injury. Transpl. Int. 26, 195–205 (2013).
Ghosh, A. K. & Vaughan, D. E. PAI-1 in tissue fibrosis. J. Cell. Physiol. 227, 493–507 (2012).
Pontrelli, P. et al. Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy. Transplantation 85, 125–134 (2008).
Diekmann, F. et al. Mammalian target of rapamycin inhibition halts the progression of proteinuria in a rat model of reduced renal mass. J. Am. Soc. Nephrol. 18, 2653–2660 (2007).
Kurdian, M. et al. Delayed mTOR inhibition with low dose of everolimus reduces TGFβ expression, attenuates proteinuria and renal damage in the renal mass reduction model. PLoS ONE 7, e32516 (2012).
Budde, K. & Gaedeke, J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Am. J. Kidney Dis. 59, 276–283 (2012).
Hallett, L., Foster, T., Liu, Z., Blieden, M. & Valentim, J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr. Med. Res. Opin. 27, 1571–1583 (2011).
Osborne, J. P., Fryer, A. & Webb, D. Epidemiology of tuberous sclerosis. Ann. NY Acad. Sci. 615, 125–127 (1991).
Curatolo, P. et al. The role of mTOR inhibitors in the treatment of patients with tuberous sclerosis complex: Evidence-based and expert opinions. Drugs 76, 551–565 (2016).
Kotulska, K., Borkowska, J. & Jozwiak, S. Possible prevention of tuberous sclerosis complex lesions. Pediatrics 132, e239–242 (2013).
Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358, 140–151 (2008).
Dabora, S. L. et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF-D levels decrease. PLoS ONE 6, e23379 (2011).
Cabrera-Lopez, C. et al. Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two years trial. Orphanet J. Rare Dis. 7, 87 (2012).
Staehler, M. et al. Nephron-sparing resection of angiomyolipoma after sirolimus pretreatment in patients with tuberous sclerosis. Int. Urol. Nephrol. 44, 1657–1661 (2012).
Bissler, J. J. et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381, 817–824 (2013).
Bissler, J. J. et al. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol. Dial. Transplant. 31, 111–119 (2016).
Pal, S. K. & Quinn, D. I. Differentiating mTOR inhibitors in renal cell carcinoma. Cancer Treat. Rev. 39, 709–719 (2013).
Hutson, T. E. et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 32, 760–767 (2014).
Flaherty, K. T. et al. BEST: a randomized Phase II study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma—a trial of the ECOG-ACRIN Cancer Research Group (E2804). J. Clin. Oncol. 33, 2384–2391 (2015).
Wander, S. A., Hennessy, B. T. & Slingerland, J. M. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest. 121, 1231–1241 (2011).
Zheng, B. et al. Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma. Cancer Lett. 357, 468–475 (2015).
Powles, T. et al. A randomised Phase 2 Study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur. Urol. 69, 450–456 (2015).
Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med. 8, 128–135 (2002).
Ghosh, A. P. et al. Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. Oncotarget 6, 17895–17910 (2015).
Nichols, L. A., Adang, L. A. & Kedes, D. H. Rapamycin blocks production of KSHV/HHV8: insights into the anti-tumor activity of an immunosuppressant drug. PLoS ONE 6, e14535 (2011).
Roy, S. & Arav-Boger, R. New cell-signaling pathways for controlling cytomegalovirus replication. Am. J. Transplant. 14, 1249–1258 (2014).
Stallone, G. et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N. Engl. J. Med. 352, 1317–1323 (2005).
Geissler, E. K. Post-transplantation malignancies: here today, gone tomorrow? Nat. Rev. Clin. Oncol. 12, 705–717 (2015).
Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label Phase 3 trial. Transplantation 100, 116–125 (2016).
Halleck, F. & Budde, K. Transplantation: Sirolimus for secondary SCC prevention in renal transplantation. Nat. Rev. Nephrol. 8, 687–689 (2012).
Hosseini-Moghaddam, S. M., Soleimanirahbar, A., Mazzulli, T., Rotstein, C. & Husain, S. Post renal transplantation Kaposi's sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy. Transpl. Infect. Dis. 14, 338–345 (2012).
Campbell, S. B., Walker, R., Tai, S. S., Jiang, Q. & Russ, G. R. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am. J. Transplant. 12, 1146–1156 (2012).
Euvrard, S. et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N. Engl. J. Med. 367, 329–339 (2012).
Di Paolo, S., Teutonico, A., Ranieri, E., Gesualdo, L. & Schena, P. F. Monitoring antitumor efficacy of rapamycin in Kaposi sarcoma. Am. J. Kidney Dis. 49, 462–470 (2007).
Yanik, E. L. et al. Sirolimus use and cancer incidence among US kidney transplant recipients. Am. J. Transplant. 15, 129–136 (2015).
Raich-Regue, D., Rosborough, B. R., Turnquist, H. R. & Thomson, A. W. Myeloid dendritic cell-specific mTORC2 deficiency enhances alloreactive Th1 and Th17 cell responses and skin graft rejection. Am J. Transplant 14, 18[Abstract 584] (2014).
Weichhart, T. et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29, 565–577 (2008).
Haidinger, M. et al. A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J. Immunol. 185, 3919–3931 (2010).
Cao, W. et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI3K-mTOR-p70S6K pathway. Nat. Immunol. 9, 1157–1164 (2008).
Boor, P. P., Metselaar, H. J., Mancham, S., van der Laan, L. J. & Kwekkeboom, J. Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions. Clin. Exp. Immunol. 174, 389–401 (2013).
Lee, K. et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–753 (2010).
Berezhnoy, A., Castro, I., Levay, A., Malek, T. R. & Gilboa, E. Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity. J. Clin. Invest. 124, 188–197 (2014).
Liacini, A., Seamone, M. E., Muruve, D. A. & Tibbles, L. A. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation 90, 1450–1457 (2010).
McInturff, A. M. et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1α. Blood 120, 3118–3125 (2012).
Vitiello, D., Neagoe, P. E., Sirois, M. G. & White, M. Effect of everolimus on the immunomodulation of the human neutrophil inflammatory response and activation. Cell. Mol. Immunol. 12, 40–52 (2015).
He, Y. et al. Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol. Biol. Cell 24, 3369–3380 (2013).
Liu, L., Gritz, D. & Parent, C. A. PKCβII acts downstream of chemoattractant receptors and mTORC2 to regulate cAMP production and myosin II activity in neutrophils. Mol. Biol. Cell 25, 1446–1457 (2014).
Zhang, L. et al. Mammalian target of rapamycin complex 1 orchestrates invariant NKT cell differentiation and effector function. J. Immunol. 193, 1759–1765 (2014).
Wei, J., Yang, K. & Chi, H. Cutting edge: discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J. Immunol. 193, 4297–4301 (2014).
Zhang, S. et al. Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production. Blood 117, 1228–1238 (2011).
Zhang, Y. et al. Rictor is required for early B cell development in bone marrow. PLoS ONE 9, e103970 (2014).
Lazorchak, A. S. et al. Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. Mol. Cell 39, 433–443 (2010).
Wang, C. et al. Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. J. Clin. Invest. 123, 1677–1693 (2013).
Wang, C. et al. Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2. J. Exp. Med. 211, 395–404 (2014).
Johnson, R. W. et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 72, 777–786 (2001).
Gonwa, T. A., Hricik, D. E., Brinker, K., Grinyo, J. M. & Schena, F. P. Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Transplantation 74, 1560–1567 (2002).
Oberbauer, R. et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 76, 364–370 (2003).
Oberbauer, R. et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl. Int. 18, 22–28 (2005).
Larson, T. S. et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am. J. Transplant. 6, 514–522 (2006).
Buchler, M. et al. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am. J. Transplant. 7, 2522–2531 (2007).
Lebranchu, Y. et al. Five-year results of a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation: the SPIESSER study. Am. J. Transplant. 12, 1801–1810 (2012).
Gatault, P. et al. Eight-year results of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation. Transpl. Int. 29, 41–50 (2016).
Ekberg, H. et al. Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am. J. Transplant. 9, 1876–1885 (2009).
Lebranchu, Y. et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study. Am. J. Transplant. 9, 1115–1123 (2009).
Lebranchu, Y. et al. Efficacy and safety of early cyclosporine conversion to sirolimus with continued MMF-four-year results of the Postconcept study. Am. J. Transplant. 11, 1665–1675 (2011).
Guba, M. et al. Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial. Transplantation 90, 175–183 (2010).
Guba, M. et al. Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36 months after transplantation. Transpl. Int. 25, 416–423 (2012).
Budde, K. et al. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 377, 837–847 (2011).
Budde, K. et al. Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study. Am. J. Transplant 15, 119–128 (2015).
Holdaas, H. et al. Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Transplantation 92, 410–418 (2011).
Weir, M. R. et al. Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial. Kidney Int. 79, 897–907 (2011).
Weir, M. R. et al. Long-term follow-up of kidney transplant recipients in the spare-the-nephron-trial. Transplantation http://dx.doi.org/10.1097/TP.0000000000001098 (2016).
Mjornstedt, L. et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am. J. Transplant 12, 2744–2753 (2012).
Mjornstedt, L. et al. Renal function three years after early conversion from a calcineurin inhibitor to everolimus: results from a randomized trial in kidney transplantation. Transpl. Int. 28, 42–51 (2015).
Budde, K. et al. Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study. Clin. Nephrol. 83, 11–21 (2015).
Reitamo, S. et al. Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial. Br. J. Dermatol. 145, 438–445 (2001).
Senior, P. A., Paty, B. W., Cockfield, S. M., Ryan, E. A. & Shapiro, A. M. Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am. J. Transplant. 5, 2318–2323 (2005).
Constantinescu, A. R., Liang, M. & Laskow, D. A. Sirolimus lowers myeloperoxidase and p-ANCA titers in a pediatric patient before kidney transplantation. Am. J. Kidney Dis. 40, 407–410 (2002).
Koening, C. L., Hernandez-Rodriguez, J., Molloy, E. S., Clark, T. M. & Hoffman, G. S. Limited utility of rapamycin in severe, refractory Wegener's granulomatosis. J. Rheumatol 36, 116–119 (2009).
Fervenza, F. C. et al. Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies. Nephrol. Dial. Transplant. 19, 1288–1292 (2004).
Kim, H. J. & Edelstein, C. L. Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside. Kidney Res. Clin. Pract. 31, 132–138 (2012).
Lieberthal, W., Fuhro, R., Andry, C., Patel, V. & Levine, J. S. Rapamycin delays but does not prevent recovery from acute renal failure: role of acquired tubular resistance. Transplantation 82, 17–22 (2006).
Lee, L. et al. Efficacy of a rapamycin analog (CCI-779) and IFN-γ in tuberous sclerosis mouse models. Genes Chromosomes Cancer 42, 213–227 (2005).
Zhang, H. et al. A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclinical renal cell carcinoma models. PLoS ONE 8, e54918 (2013).
Chiarini, F., Evangelisti, C., McCubrey, J. A. & Martelli, A. M. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol. Sci. 36, 124–135 (2015).
Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).
Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).
Mita, M. M. et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J. Clin. Oncol. 26, 361–367 (2008).
Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909–918 (2004).
Acknowledgements
D.F.'s work is supported by an American Society of Nephrology Ben Lipps Research Fellowship. N.M.R.'s work is supported by an NHMRC C.J. Martin Fellowship, an American Society of Transplantation Basic Science Fellowship, an American Heart Association award (13 POST1452003), and by a Joseph A. Patrick Fellowship from the Starzl Transplantation Institute. A.W.T. is in receipt of research grants from the NIH (R56 AI126377; U01 AI91197 and U01 AI102456) and the US Department of Defense (W81XWH-15-2-0027). The authors' work is also supported by the German Research Foundation: CRC 1140 KidGEM (F.G., T.B.H.), Heisenberg program and CRC 992 (T.B.H.); by the European Research Council (T.B.H.); and by the Excellence Initiative of the German Federal and State Governments (EXC 294 to T.B.H.). We thank Ms. Miriam Freeman for excellent administrative support.
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D.F., N.M.R., and F.G. are co-first authors and T.B.H. and A.W.T are co-senior authors of this Review. D.F., N.M.R. and F.G. contributed equally to writing the article. T.B.H. and A.W.T. researched literature for the article, provided substantial discussion of the content and contributed equally to review and/or editing of the manuscript before and after submission.
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Fantus, D., Rogers, N., Grahammer, F. et al. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat Rev Nephrol 12, 587–609 (2016). https://doi.org/10.1038/nrneph.2016.108
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DOI: https://doi.org/10.1038/nrneph.2016.108
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