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Diverse origins of the myofibroblast—implications for kidney fibrosis

Nature Reviews Nephrology volume 11, pages 233–244 (2015)Cite this article

Subjects

Key Points

  • Myofibroblasts involved in kidney fibrosis might originate from diverse origins, including bone marrow-derived fibroblasts, tubular epithelial cells, endothelial cells, pericytes and interstitial fibroblasts

  • Independent studies have shown that myofibroblasts can be derived from either one or more sources, irrespective of the nature of the initial damage responsible for the induction of kidney fibrosis

  • The diversity of myofibroblast progenitors in kidney fibrosis might be relevant for the development of novel therapies

  • Systemic therapies have been developed that can inhibit myofibroblast accumulation and fibrotic development; however, the efficacy and safety of these therapies in chronic kidney disease is not clear

  • Targeting strategies to support resident and circulating cells in maintaining or regaining their original functional differentiation state and resisting transition to a myofibroblast phenotype might prevent or reverse fibrosis

Abstract

Fibrosis is the common end point of chronic kidney disease. The persistent production of inflammatory cytokines and growth factors leads to an ongoing process of extracellular matrix production that eventually disrupts the normal functioning of the organ. During fibrosis, the myofibroblast is commonly regarded as the predominant effector cell. Accumulating evidence has demonstrated a diverse origin of myofibroblasts in kidney fibrosis. Proposed major contributors of myofibroblasts include bone marrow-derived fibroblasts, tubular epithelial cells, endothelial cells, pericytes and interstitial fibroblasts; the published data, however, have not yet clearly defined the relative contribution of these different cellular sources. Myofibroblasts have been reported to originate from various sources, irrespective of the nature of the initial damage responsible for the induction of kidney fibrosis. Here, we review the possible relevance of the diversity of myofibroblast progenitors in kidney fibrosis and the implications for the development of novel therapeutic approaches. Specifically, we discuss the current status of preclinical and clinical antifibrotic therapy and describe targeting strategies that might help support resident and circulating cells to maintain or regain their original functional differentiation state. Such strategies might help these cells resist their transition to a myofibroblast phenotype to prevent, or even reverse, the fibrotic state.

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Figure 1: Differentiation steps of fibroblasts towards myofibroblast subtypes.
Figure 2: Expression of fibroblast markers only partially overlap in kidney fibrosis.
Figure 3: Schematic of the Cre–lox system used to trace FOXD1-positive pericytes.
Figure 4: Potential origins of myofibroblast progenitors.

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References

  1. Kok, H. M., Falke, L. L., Goldschmeding, R. & Nguyen, T. Q. Targeting CTGF, EGF and PDGF pathways to prevent progression of kidney disease. Nat. Rev. Nephrol. 10, 700–711 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Hakroush, S. et al. Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. Am. J. Pathol. 175, 1883–1895 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Thannickal, V. J. Aging, antagonistic pleiotropy and fibrotic disease. Int. J. Biochem. Cell Biol. 42, 1398–1400 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ryu, J. H. & Daniels, C. E. Advances in the management of idiopathic pulmonary fibrosis. F1000 Med. Rep. 2, 28 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. 8, 241–276 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Novak, M. L. & Koh, T. J. Macrophage phenotypes during tissue repair. J. Leukoc. Biol. 93, 875–881 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Strutz, F. & Muller, G. A. Mechanisms of renal fibrogenesis. in Immunological Renal Diseases 2nd edn (Eds Neilson, E.G. & Couser, W.G.) 73–101 (Lippincott-Raven, 2001).

    Google Scholar 

  9. Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Micallef, L. et al. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair 5 (Suppl. 1), S5 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. Inflammatory processes in renal fibrosis. Nat. Rev. Nephrol. 10, 493–503 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Meran, S. & Steadman, R. Fibroblasts and myofibroblasts in renal fibrosis. Int. J. Exp. Pathol. 92, 158–167 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boor, P. & Floege, J. The renal (myo-)fibroblast: a heterogeneous group of cells. Nephrol. Dial. Transplant. 27, 3027–3036 (2012).

    Article  PubMed  Google Scholar 

  16. Gabbiani, G. & Majno, G. Dupuytren's contracture: fibroblast contraction? An ultrastructural study. Am. J. Pathol. 66, 131–146 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Eyden, B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J. Cell. Mol. Med. 12, 22–37 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Duffield, J. S. Cellular and molecular mechanisms in kidney fibrosis. J. Clin. Invest. 124, 2299–2306 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807–1816 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lin, S. L., Kisseleva, T., Brenner, D. A. & Duffield, J. S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am. J. Pathol. 173, 1617–1627 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hinz, B. The myofibroblast: paradigm for a mechanically active cell. J. Biomech. 43, 146–155 (2010).

    Article  PubMed  Google Scholar 

  22. Strutz, F. et al. Identification and characterization of a fibroblast marker: FSP1. J. Cell Biol. 130, 393–405 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Leader, M., Collins, M., Patel, J. & Henry, K. Vimentin: an evaluation of its role as a tumour marker. Histopathology 11, 63–72 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Osterreicher, C. H. et al. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl Acad. Sci. USA 108, 308–313 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Mor-Vaknin, N., Punturieri, A., Sitwala, K. & Markovitz, D. M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 5, 59–63 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Lewandoski, M. Conditional control of gene expression in the mouse. Nat. Rev. Genet. 2, 743–755 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Dressler, G. R. Advances in early kidney specification, development and patterning. Development 136, 3863–3874 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Asada, N. et al. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J. Clin. Invest. 121, 3981–3990 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sauer, B. Inducible gene targeting in mice using the Cre/lox system. Methods 14, 381–392 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Picard, N., Baum, O., Vogetseder, A., Kaissling, B. & Le Hir, M. Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat. Histochem. Cell Biol. 130, 141–155 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Faulkner, J. L., Szcykalski, L. M., Springer, F. & Barnes, J. L. Origin of interstitial fibroblasts in an accelerated model of angiotensin II-induced renal fibrosis. Am. J. Pathol. 167, 1193–1205 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lebleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Khairoun, M. et al. Renal ischemia-reperfusion induces a dysbalance of angiopoietins, accompanied by proliferation of pericytes and fibrosis. Am. J. Physiol. Renal Physiol. 305, F901–F910 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Kida, Y. & Duffield, J. S. Pivotal role of pericytes in kidney fibrosis. Clin. Exp. Pharmacol. Physiol. 38, 467–473 (2011).

    Article  PubMed  CAS  Google Scholar 

  37. Schlondorff, D. The glomerular mesangial cell: an expanding role for a specialized pericyte. FASEB J. 1, 272–281 (1987).

    Article  CAS  PubMed  Google Scholar 

  38. Sam, R. et al. Glomerular epithelial cells transform to myofibroblasts: early but not late removal of TGF-β1 reverses transformation. Transl. Res. 148, 142–148 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Whiteside, C. et al. Regulation of mesangial cell alpha-smooth muscle actin expression in 3-dimensional matrix by high glucose and growth factors. Nephron Exp. Nephrol. 109, e46–e56 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Alpers, C. E., Hudkins, K. L., Gown, A. M. & Johnson, R. J. Enhanced expression of “muscle-specific” actin in glomerulonephritis. Kidney Int. 41, 1134–1142 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Matsubara, T. et al. Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab. Invest. 86, 357–368 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ng, Y. Y. et al. Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation. Nephrol. Dial. Transplant. 14, 2860–2872 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Ng, Y. Y. et al. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int. 54, 864–876 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Yamaguchi, Y. et al. Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am. J. Kidney Dis. 54, 653–664 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Bariety, J. et al. Glomerular epithelial-mesenchymal transdifferentiation in pauci-immune crescentic glomerulonephritis. Nephrol. Dial. Transplant. 18, 1777–1784 (2003).

    Article  PubMed  Google Scholar 

  48. Rastaldi, M. P. et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int. 62, 137–146 (2002).

    Article  PubMed  Google Scholar 

  49. Vongwiwatana, A., Tasanarong, A., Rayner, D. C., Melk, A. & Halloran, P. F. Epithelial to mesenchymal transition during late deterioration of human kidney transplants: the role of tubular cells in fibrogenesis. Am. J. Transplant. 5, 1367–1374 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, C. L. et al. Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines. Exp. Cell Res. 316, 1109–1118 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Tasanarong, A., Kongkham, S. & Khositseth, S. Dual inhibiting senescence and epithelial-to-mesenchymal transition by erythropoietin preserve tubular epithelial cell regeneration and ameliorate renal fibrosis in unilateral ureteral obstruction. Biomed. Res. Int. 2013, 308130 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yang, J. & Liu, Y. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J. Am. Soc. Nephrol. 13, 96–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Zeisberg, M. et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964–968 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li, L., Zepeda-Orozco, D., Black, R. & Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767–1778 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Koesters, R. et al. Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am. J. Pathol. 177, 632–643 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Galichon, P., Finianos, S. & Hertig, A. EMT-MET in renal disease: should we curb our enthusiasm? Cancer Lett. 341, 24–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Kriz, W., Kaissling, B. & Le Hir, M. Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J. Clin. Invest. 121, 468–474 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Smeets, B. et al. Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells. J. Am. Soc. Nephrol. 20, 2604–2615 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hackl, M. J. et al. Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in new mouse models with fluorescent lineage tags. Nat. Med. 19, 1661–1666 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schulte, K. et al. Origin of parietal podocytes in atubular glomeruli mapped by lineage tracing. J. Am. Soc. Nephrol. 25, 129–141 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Burford, J. L. et al. Intravital imaging of podocyte calcium in glomerular injury and disease. J. Clin. Invest. 124, 2050–2058 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Eremina, V. et al. Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J. Am. Soc. Nephrol. 17, 724–735 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Sakamaki, Y. et al. Injured kidney cells express SM22α (transgelin): Unique features distinct from alpha-smooth muscle actin (αSMA). Nephrology (Carlton) 16, 211–218 (2011).

    Article  Google Scholar 

  66. Piera-Velazquez, S., Li, Z. & Jimenez, S. A. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am. J. Pathol. 179, 1074–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li, J., Qu, X. & Bertram, J. F. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am. J. Pathol. 175, 1380–1388 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Phua, Y. L., Martel, N., Pennisi, D. J., Little, M. H. & Wilkinson, L. Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins. J. Pathol. 229, 685–696 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Curci, C. et al. Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway. Nephrol. Dial. Transplant. 29, 799–808 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Bellini, A. & Mattoli, S. The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab. Invest. 87, 858–870 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Lee, C. H., Shah, B., Moioli, E. K. & Mao, J. J. CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J. Clin. Invest. 120, 3340–3349 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yang, L. et al. Bone marrow-derived mesenchymal stem cells differentiate to hepatic myofibroblasts by transforming growth factor-beta1 via sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis. Am. J. Pathol. 181, 85–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Reich, B. et al. Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 84, 78–89 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Broekema, M. et al. Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. J. Am. Soc. Nephrol. 18, 165–175 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Grimm, P. C. et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N. Engl. J. Med. 345, 93–97 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Rienstra, H. et al. Donor and recipient origin of mesenchymal and endothelial cells in chronic renal allograft remodeling. Am. J. Transplant. 9, 463–472 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Roufosse, C. et al. Bone marrow-derived cells do not contribute significantly to collagen I synthesis in a murine model of renal fibrosis. J. Am. Soc. Nephrol. 17, 775–782 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Lin, S. L., Castano, A. P., Nowlin, B. T., Lupher, M. L. Jr & Duffield, J. S. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J. Immunol. 183, 6733–6743 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Eddy, A. A., Lopez-Guisa, J. M., Okamura, D. M. & Yamaguchi, I. Investigating mechanisms of chronic kidney disease in mouse models. Pediatr. Nephrol. 27, 1233–1247 (2012).

    Article  PubMed  Google Scholar 

  80. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Chang, L. et al. Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. Proc. Natl Acad. Sci. USA 109, 6993–6998 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Eddy, A. A. The origin of scar-forming kidney myofibroblasts. Nat. Med. 19, 964–966 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Zeisberg, M. & Duffield, J. S. Resolved: EMT produces fibroblasts in the kidney. J. Am. Soc. Nephrol. 21, 1247–1253 (2010).

    Article  PubMed  Google Scholar 

  84. Tampe, D. & Zeisberg, M. Potential approaches to reverse or repair renal fibrosis. Nat. Rev. Nephrol. 10, 226–237 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Distler, J. H. & Distler, O. Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann. Rheum. Dis. 69 (Suppl. 1), i48–i51 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Prakash, J. et al. Novel therapeutic targets for the treatment of tubulointerstitial fibrosis. Current Signal Transduction Therapy 3, 97–111 (2014).

    Article  Google Scholar 

  87. Bansal, R., Prakash, J., De Ruiter, M. & Poelstra, K. Targeted recombinant fusion proteins of IFNγ and mimetic IFNγ with PDGFbetaR bicyclic peptide inhibits liver fibrogenesis in vivo. PLoS ONEe 9, e89878 (2014).

    Article  CAS  Google Scholar 

  88. Hagens, W. I. et al. Targeting 15d-prostaglandin J2 to hepatic stellate cells: two options evaluated. Pharm. Res. 24, 566–574 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Christensen, E. I., Birn, H., Storm, T., Weyer, K. & Nielsen, R. Endocytic receptors in the renal proximal tubule. Physiology (Bethesda) 27, 223–236 (2012).

    CAS  Google Scholar 

  90. Prakash, J. et al. Inhibition of renal rho kinase attenuates ischemia/reperfusion-induced injury. J. Am. Soc. Nephrol. 19, 2086–2097 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shillingford, J. M., Leamon, C. P., Vlahov, I. R. & Weimbs, T. Folate-conjugated rapamycin slows progression of polycystic kidney disease. J. Am. Soc. Nephrol. 23, 1674–1681 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Prakash, J. et al. Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in renal tubular cells: a novel strategy to treat renal fibrosis. J. Pharmacol. Exp. Ther. 319, 8–19 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Lin, Y. et al. Targeted drug delivery to renal proximal tubule epithelial cells mediated by 2-glucosamine. J. Control Release 167, 148–156 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Wang, X. et al. Effects of mycophenolic acid-glucosamine conjugates on the base of kidney targeted drug delivery. Int. J. Pharm. 456, 223–234 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Floege, J., Eitner, F. & Alpers, C. E. A new look at platelet-derived growth factor in renal disease. J. Am. Soc. Nephrol. 19, 12–23 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Greupink, R. et al. Mannose-6-phosphate/insulin-Like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells. Pharm. Res. 23, 1827–1834 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Moreno, M. et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 51, 942–952 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. van Beuge, M. M. et al. Enhanced effectivity of an ALK5-inhibitor after cell-specific delivery to hepatic stellate cells in mice with liver injury. PLoS ONE 8, e56442 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dolman, M. E., Harmsen, S., Storm, G., Hennink, W. E. & Kok, R. J. Drug targeting to the kidney: Advances in the active targeting of therapeutics to proximal tubular cells. Adv. Drug Deliv. Rev. 62, 1344–1357 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Leeuwis, J. W., Nguyen, T. Q., Dendooven, A., Kok, R. J. & Goldschmeding, R. Targeting podocyte-associated diseases. Adv. Drug Deliv. Rev. 62, 1325–1336 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Scindia, Y. M., Deshmukh, U. S. & Bagavant, H. Mesangial pathology in glomerular disease: targets for therapeutic intervention. Adv. Drug Deliv. Rev. 62, 1337–1343 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Qin, W. et al. TGF-beta/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J. Am. Soc. Nephrol. 22, 1462–1474 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Trachtman, H. et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int. 79, 1236–1243 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. A Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis(FSGS). ClinicalTrials.gov[online] (2014).

  105. Adler, S. G. et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin. J. Am. Soc. Nephrol. 5, 1420–1428 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2071–2082 (2014).

    Article  PubMed  CAS  Google Scholar 

  107. Liu, N. et al. Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J. Am. Soc. Nephrol. 23, 854–867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Elmholdt, T. R., Buus, N. H., Ramsing, M. & Olesen, A. B. Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: an open-label non-randomized, uncontrolled clinical trial. J. Eur. Acad. Dermatol. Venereol. 27, 779–784 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Illouz, F., Braun, D., Briet, C., Schweizer, U. & Rodien, P. Endocrine side-effects of anti-cancer drugs: thyroid effects of tyrosine kinase inhibitors. Eur. J. Endocrinol. 171, R91–R99 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Hartmann, J. T., Haap, M., Kopp, H. G. & Lipp, H. P. Tyrosine kinase inhibitors—a review on pharmacology, metabolism and side effects. Curr. Drug Metab. 10, 470–481 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Hong, S. et al. Risk of treatment-related deaths with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis of 41 randomized controlled trials. Onco. Targets Ther. 7, 1851–1867 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Connolly, E. C. et al. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TbetaRI/II kinase inhibition with LY2109761. Cancer Res. 71, 2339–2349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dolman, M. E. et al. Imatinib-ULS-lysozyme: a proximal tubular cell-targeted conjugate of imatinib for the treatment of renal diseases. J. Control Release 157, 461–468 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Prakash, J. et al. Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis. Pharm. Res. 25, 2427–2439 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Dankers, P. Y. et al. Hierarchical formation of supramolecular transient networks in water: a modular injectable delivery system. Adv. Mater. 24, 2703–2709 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Lebleu, V. S., Sugimoto, H., Miller, C. A., Gattone, V. H. 2nd & Kalluri, R. Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease. Lab. Invest. 88, 284–292 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Stokman, G. et al. Epac-Rap signaling reduces oxidative stress in the tubular epithelium. J. Am. Soc. Nephrol. 25, 1474–1485 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang, X. et al. Mechanistic studies of a novel mycophenolic Acid-glucosamine conjugate that attenuates renal ischemia/reperfusion injury in rat. Mol. Pharm. 11, 3503–3514 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Yuan, Z. X. et al. Randomly 50% N-acetylated low molecular weight chitosan as a novel renal targeting carrier. J. Drug Target. 15, 269–278 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Suzuki, K. et al. Specific renal delivery of sugar-modified low-molecular-weight peptides. J. Pharmacol. Exp. Ther. 288, 888–897 (1999).

    CAS  PubMed  Google Scholar 

  122. Scindia, Y., Deshmukh, U., Thimmalapura, P. R. & Bagavant, H. Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus. Arthritis Rheum. 58, 3884–3891 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Suana, A. J. et al. Single application of low-dose mycophenolate mofetil-OX7-immunoliposomes ameliorates experimental mesangial proliferative glomerulonephritis. J. Pharmacol. Exp. Ther. 337, 411–422 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Asgeirsdottir, S. A. et al. Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes. Am. J. Physiol. Renal Physiol. 294, F554–F561 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Hauser, P. V. et al. Novel siRNA delivery system to target podocytes in vivo. PLoS One 5, e9463 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands

    Lucas L. Falke, Roel Goldschmeding & Tri Q. Nguyen

  2. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, Utrecht, 3584 CG, Netherlands

    Shima Gholizadeh & Robbert J. Kok

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  1. Lucas L. Falke
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  2. Shima Gholizadeh
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  3. Roel Goldschmeding
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  5. Tri Q. Nguyen
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Contributions

L.L.F., S.G., R.G., R.J.K. and T.Q.N. researched data for the article. All authors provided substantial contributions to discussions of its content and wrote the article. L.L.F., R.G., R.J.K. and T.Q.N. undertook review and/or editing of the manuscript before submission. L.L.F. and S.G. contributed equally. R.J.K. and T.Q.N. contributed equally.

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Correspondence to Roel Goldschmeding.

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Falke, L., Gholizadeh, S., Goldschmeding, R. et al. Diverse origins of the myofibroblast—implications for kidney fibrosis. Nat Rev Nephrol 11, 233–244 (2015). https://doi.org/10.1038/nrneph.2014.246

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