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  • Review Article
  • Published:

Novel targets of antifibrotic and anti-inflammatory treatment in CKD

Nature Reviews Nephrology volume 10, pages 257–267 (2014)Cite this article

Subjects

Key Points

  • The incidence of chronic kidney disease (CKD) has increased dramatically over the past 10 years, and new strategies for slowing its progression are urgently needed

  • Many novel approaches to control renal fibrosis in CKD are currently in clinical development

  • NADPH oxidase isoforms have emerged as important mediators of vascular dysfunction, inflammation, and fibrosis in CKD

  • New insights into the role of vascular calcification in the pathogenesis of CKD have led to novel therapeutic approaches, which are under preclinical and clinical development

  • Further animal studies and clinical trials are urgently needed to determine the potential beneficial effects of activating energy-sensing molecules in slowing the progression of CKD

  • Mitochondrial function and biogenesis are now considered as active players in the development of CKD

Abstract

Chronic kidney disease (CKD) is becoming a worldwide epidemic, driven largely by the dramatic rise in the prevalence of diabetes and obesity. Novel targets and treatments for CKD are, therefore, desperately needed—to both mitigate the burden of this disease in the general population and reduce the necessity for renal replacement therapy in individual patients. This Review highlights new insights into the mechanisms that contribute to CKD, and approaches that might facilitate the development of disease-arresting therapies for CKD. Particular focus is given to therapeutic approaches using antifibrotic agents that target the transforming growth factor β superfamily. In addition, we discuss new insights regarding the roles of vascular calcification, the NADPH oxidase family, and inflammation in the pathogenesis of CKD. We also highlight a new understanding regarding kidney energy sensing pathways (AMPK, sirtuins, and mTOR) in a variety of kidney diseases and how they are linked to inflammation and fibrosis. Finally, exciting new insights have been made into the role of mitochondrial function and mitochondrial biogenesis in relation to progressive kidney disease. Prospective therapeutics based on these findings will hopefully renew hope for clinicians and patients in the near future.

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Figure 1: Specific targets and potential therapeutic strategies to inhibit or slow the progression of CKD.

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References

  1. Jha, V. et al. Chronic kidney disease: global dimension and perspectives. Lancet 382, 260–272 (2013).

    Article  PubMed  Google Scholar 

  2. ReporterLinker. Dialysis Market [(Hemodialysis—Machine, Dialyzer, Bloodlines, Concentrates, Services), (Peritoneal Dialysis—Cycler, Catheter, Dialysate, CCPD, CAPD, IPD), (End Users—Hospital, Independent Dialysis Center, Home Dialysis)]—Global Forecast to 2018 [online], (2013).

  3. Ziyadeh, F. N. et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice. Proc. Natl Acad. Sci. USA 97, 8015–8020 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen, S. et al. Reversibility of established diabetic glomerulopathy by anti-TGF-β antibodies in db/db mice. Biochem. Biophys. Res. Commun. 300, 16–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Guan, Q. et al. Reduction of chronic rejection of renal allografts by anti-transforming growth factor-β antibody therapy in a rat model. Am. J. Physiol. Renal Physiol. 305, F199–F207 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Williams, S. J. et al. 3′,4′-Bis-difluoromethoxycinnamoylanthranilate (FT061): an orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy. Bioorg. Med. Chem. Lett. 23, 6868–6873 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Sharma, K., McCue, P. & Dunn, S. R. Diabetic kidney disease in the db/db mouse. Am. J. Physiol. Renal Physiol. 284, F1138–F1144 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Negri, A. L. Prevention of progressive fibrosis in chronic renal diseases: antifibrotic agents. J. Nephrol. 17, 496–503 (2004).

    CAS  PubMed  Google Scholar 

  9. Zeisberg, M. & Kalluri, R. Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. Pediatr. Nephrol. 23, 1395–1398 (2008).

    Article  PubMed  Google Scholar 

  10. Liu, Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 69, 213–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Border, W. A. & Noble, N. A. Transforming growth factor β in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Sharma, K., Jin, Y., Guo, J. & Ziyadeh, F. N. Neutralization of TGF-β by anti-TGF-β antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45, 522–530 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Ma, L. J. et al. Divergent effects of low versus high dose anti-TGF-β antibody in puromycin aminonucleoside nephropathy in rats. Kidney Int. 65, 106–115 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Juarez, P. et al. Soluble β glycan reduces renal damage progression in db/db mice. Am. J. Physiol. Renal Physiol. 292, F321–F329 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Kushibiki, T., Nagata-Nakajima, N., Sugai, M., Shimizu, A. & Tabata, Y. Delivery of plasmid DNA expressing small interference RNA for TGF-β type II receptor by cationized gelatin to prevent interstitial renal fibrosis. J. Control. Release 105, 318–331 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  18. Boor, P. & Floege, J. Chronic kidney disease growth factors in renal fibrosis. Clin. Exp. Pharmacol. Physiol. 38, 441–450 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Guha, M., Xu, Z. G., Tung, D., Lanting, L. & Natarajan, R. Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J. 21, 3355–3368 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Luo, G. H. et al. Inhibition of connective tissue growth factor by small interfering RNA prevents renal fibrosis in rats undergoing chronic allograft nephropathy. Transplant. Proc. 40, 2365–2369 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  23. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  24. US National Library of Medicine. ClinicalTrials.gov[online], (2009).

  25. Ramachandrarao, S. P. et al. Pirfenidone is renoprotective in diabetic kidney disease. J. Am. Soc. Nephrol. 20, 1765–1775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen, J. F. et al. Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats. Am. J. Physiol. Renal Physiol. 304, F676–F685 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Sharma, K. et al. Pirfenidone for diabetic nephropathy. J. Am. Soc. Nephrol. 22, 1144–1151 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kelly, D. J., Zhang, Y., Gow, R. & Gilbert, R. E. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J. Am. Soc. Nephrol. 15, 2619–2629 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Tao, Y. et al. Tranilast attenuates chronic cyclosporine nephrotoxicity in rats. Transplant. Proc. 41, 4373–4375 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Tan, S. M., Zhang, Y., Cox, A. J., Kelly, D. J. & Qi, W. Tranilast attenuates the up-regulation of thioredoxin-interacting protein and oxidative stress in an experimental model of diabetic nephropathy. Nephrol. Dial. Transplant. 26, 100–110 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Kaneyama, T., Kobayashi, S., Aoyagi, D. & Ehara, T. Tranilast modulates fibrosis, epithelial-mesenchymal transition and peritubular capillary injury in unilateral ureteral obstruction rats. Pathology 42, 564–573 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Soma, J., Sato, K., Saito, H. & Tsuchiya, Y. Effect of tranilast in early-stage diabetic nephropathy. Nephrol. Dial. Transplant. 21, 2795–2799 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Soma, J., Sugawara, T., Huang, Y. D., Nakajima, J. & Kawamura, M. Tranilast slows the progression of advanced diabetic nephropathy. Nephron 92, 693–698 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, Y. et al. FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy. Eur. J. Heart Fail. 14, 549–562 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Gilbert, R. E. et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS ONE 7, e47160 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Australian New Zealand Clinical Trials Registry. Anzctr.org[online], (2013).

  37. Meng, X. M., Chung, A. C. & Lan, H. Y. Role of the TGF-β /BMP-7/Smad pathways in renal diseases. Clin. Sci. (Lond.) 124, 243–254 (2013).

    Article  CAS  Google Scholar 

  38. Tsuchida, K., Zhu, Y., Siva, S., Dunn, S. R. & Sharma, K. Role of Smad4 on TGF-β -induced extracellular matrix stimulation in mesangial cells. Kidney Int. 63, 2000–2009 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Zhong, X. et al. miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia 56, 663–674 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Putta, S. et al. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J. Am. Soc. Nephrol. 23, 458–469 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vukicevic, S. et al. Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J. Clin. Invest. 102, 202–214 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Spanjol, J. et al. Bone morphogenetic protein-7 expression in human pyelonephritis. Coll. Antropol. 34 (Suppl. 2), 61–64 (2010).

    PubMed  Google Scholar 

  43. Bramlage, C. P. et al. Bone morphogenetic protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis. BMC Nephrol. 11, 31 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zeisberg, M. et al. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Med. 9, 964–968 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Tanaka, M. et al. Expression of BMP-7 and USAG-1 (a BMP antagonist) in kidney development and injury. Kidney Int. 73, 181–191 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Gong, R., Rifai, A., Tolbert, E. M., Centracchio, J. N. & Dworkin, L. D. Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial fibrosis. J. Am. Soc. Nephrol. 14, 3047–3060 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Mizuno, S., Matsumoto, K., Kurosawa, T., Mizuno-Horikawa, Y. & Nakamura, T. Reciprocal balance of hepatocyte growth factor and transforming growth factor-β 1 in renal fibrosis in mice. Kidney Int. 57, 937–948 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Dworkin, L. D. et al. Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury. Kidney Int. 65, 409–419 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Kuroiwa, T. et al. Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease. Arthritis Res. Ther. 8, R123 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang, H. Y. et al. Hepatocyte growth factor-induced amelioration in chronic renal failure is associated with reduced expression of α-smooth muscle actin. Ren. Fail. 34, 862–870 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Okada, H. et al. Transgene-derived hepatocyte growth factor attenuates reactive renal fibrosis in aristolochic acid nephrotoxicity. Nephrol. Dial. Transplant. 18, 2515–2523 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Gong, R. et al. Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of macrophage chemoattractant protein-1 and RANTES. J. Am. Soc. Nephrol. 15, 2868–2881 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Mizuno, S. & Nakamura, T. Suppressions of chronic glomerular injuries and TGF-β 1 production by HGF in attenuation of murine diabetic nephropathy. Am. J. Physiol. Renal Physiol. 286, F134–F143 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Tu, Y. et al. Cell division autoantigen 1 enhances signaling and the profibrotic effects of transforming growth factor-β in diabetic nephropathy. Kidney Int. 79, 199–209 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Chai, Z. et al. Genetic deletion of cell division autoantigen 1 retards diabetes-associated renal injury. J. Am. Soc. Nephrol. 24, 1782–1792 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chai, Z., Sarcevic, B., Mawson, A. & Toh, B. H. SET-related cell division autoantigen-1 (CDA1) arrests cell growth. J. Biol. Chem. 276, 33665–33674 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. 121, 4393–4408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Komaba, H. & Fukagawa, M. The role of FGF23 in CKD—with or without Klotho. Nat. Rev. Nephrol. 8, 484–490 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Hu, M. C., Kuro-o, M. & Moe, O. W. Klotho and kidney disease. J. Nephrol. 23 (Suppl. 16), S136–S144 (2010).

    PubMed  PubMed Central  Google Scholar 

  60. Gutierrez, O. et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J. Am. Soc. Nephrol. 16, 2205–2215 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Shigematsu, T. et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am. J. Kidney Dis. 44, 250–256 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Hu, M. C. et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 22, 124–136 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fischer, S. S. et al. Hyperaldosteronism in Klotho-deficient mice. Am. J. Physiol. Renal Physiol. 299, F1171–F1177 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Voelkl, J. et al. Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. J. Clin. Invest. 123, 812–822 (2013).

    PubMed  PubMed Central  Google Scholar 

  65. Jaffe, I. Z., Tintut, Y., Newfell, B. G., Demer, L. L. & Mendelsohn, M. E. Mineralocorticoid receptor activation promotes vascular cell calcification. Arterioscler. Thromb. Vasc. Biol. 27, 799–805 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Sanz-Rosa, D. et al. Participation of aldosterone in the vascular inflammatory response of spontaneously hypertensive rats: role of the NFκB/IκB system. J. Hypertens. 23, 1167–1172 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Zhou, L., Li, Y., Zhou, D., Tan, R. J. & Liu, Y. Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. J. Am. Soc. Nephrol. 24, 771–785 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rosca, M. G. et al. Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am. J. Physiol. Renal Physiol. 289, F420–F430 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Brouwers, O. et al. Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation end products and oxidative stress in diabetic rats. J. Biol. Chem. 286, 1374–1380 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Coughlan, M. T. et al. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J. Am. Soc. Nephrol. 20, 742–752 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Montezano, A. C. & Touyz, R. M. Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies. Ann. Med. 44 (Suppl. 1), S2–S16 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Popolo, A., Autore, G., Pinto, A. & Marzocco, S. Oxidative stress in patients with cardiovascular disease and chronic renal failure. Free Radic. Res. 47, 346–356 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. You, Y. H. et al. Role of Nox2 in diabetic kidney disease. Am. J. Physiol. Renal Physiol. 304, F840–F848 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sharma, K. et al. Adiponectin regulates albuminuria and podocyte function in mice. J. Clin. Invest. 118, 1645–1656 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Babelova, A. et al. Role of Nox4 in murine models of kidney disease. Free Radic. Biol. Med. 53, 842–853 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Gorin, Y. & Block, K. Nox as a target for diabetic complications. Clin. Sci. (Lond.) 125, 361–382 (2013).

    Article  CAS  Google Scholar 

  78. Sedeek, M., Nasrallah, R., Touyz, R. M. & Hebert, R. L. NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J. Am. Soc. Nephrol. 24, 1512–1518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Holterman, C. E. et al. Nephropathy and elevated BP in mice with podocyte-specific NADPH oxidase 5 expression. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2013040371.

  80. Sedeek, M. et al. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am. J. Physiol. Renal Physiol. 299, F1348–F1358 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Sedeek, M. et al. Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of type 2 diabetes. Clin. Sci. (Lond.) 124, 191–202 (2013).

    Article  CAS  Google Scholar 

  82. Aoyama, T. et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56, 2316–2327 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Gray, S. P. et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation 127, 1888–1902 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  85. Nlandu Khodo, S. et al. NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury. J. Am. Soc. Nephrol. 23, 1967–1976 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Volpini, R. A., Costa, R. S., da Silva, C. G. & Coimbra, T. M. Inhibition of nuclear factor-κB activation attenuates tubulointerstitial nephritis induced by gentamicin. Nephron Physiol. 98, 97–106 (2004).

    Article  CAS  Google Scholar 

  87. Fujihara, C. K. et al. Chronic inhibition of nuclear factor-κB attenuates renal injury in the 5/6 renal ablation model. Am. J. Physiol. Renal Physiol. 292, F92–F99 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Ding, W., Yang, L., Zhang, M. & Gu, Y. Chronic inhibition of nuclear factor κB attenuates aldosterone/salt-induced renal injury. Life Sci. 90, 600–606 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Kim, J. E. et al. Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. PLoS ONE 8, e62068 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Briffa, J. F., McAinch, A. J., Poronnik, P. & Hryciw, D. H. Adipokines as a link between obesity and chronic kidney disease. Am. J. Physiol. Renal Physiol. 305, F1629–F1636 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Li, Y. et al. Protective effect of celastrol in rat cerebral ischemia model: down-regulating p-JNK, p-c-Jun and NF-κB. Brain Res. 1464, 8–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Decleves, A. E., Mathew, A. V., Cunard, R. & Sharma, K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J. Am. Soc. Nephrol. 22, 1846–1855 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Deji, N. et al. Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am. J. Physiol. Renal Physiol. 296, F118–F126 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Kambham, N., Markowitz, G. S., Valeri, A. M., Lin, J. & D'Agati, V. D. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 59, 1498–1509 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Goumenos, D. S. et al. Early histological changes in the kidney of people with morbid obesity. Nephrol. Dial. Transplant. 24, 3732–3738 (2009).

    Article  PubMed  Google Scholar 

  96. Chagnac, A. et al. Glomerular hemodynamics in severe obesity. Am. J. Physiol. Renal Physiol. 278, F817–F822 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Kershaw, E. E. & Flier, J. S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89, 2548–2556 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Ruster, C. & Wolf, G. The role of the renin-angiotensin-aldosterone system in obesity-related renal diseases. Semin. Nephrol. 33, 44–53 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Ruster, C. & Wolf, G. Adipokines promote chronic kidney disease. Nephrol. Dial. Transplant. 28 (Suppl. 4), iv8–iv14 (2013).

    PubMed  Google Scholar 

  100. O'Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Kadowaki, T., Yamauchi, T. & Kubota, N. The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett. 582, 74–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Decleves, A. E. et al. Regulation of lipid accumulation by AMK-activated kinase in high fat diet-induced kidney injury. Kidney Int. http://dx.doi.org/10.1038/ki.2013.462.

  103. Wang, S. et al. AMPKα2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ. Res. 106, 1117–1128 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Eid, A. A. et al. AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes. J. Biol. Chem. 285, 37503–37512 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dugan, L. L. et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest. 123, 4888–4899 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mishra, R. et al. AMP-activated protein kinase inhibits transforming growth factor-β-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J. Biol. Chem. 283, 10461–10469 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Sanchez, A. P. et al. Role of the USF1 transcription factor in diabetic kidney disease. Am. J. Physiol. Renal Physiol. 301, F271–F279 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhu, Y., Casado, M., Vaulont, S. & Sharma, K. Role of upstream stimulatory factors in regulation of renal transforming growth factor-β1. Diabetes 54, 1976–1984 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Yang, Z., Kahn, B. B., Shi, H. & Xue, B. Z. Macrophage α1 AMP-activated protein kinase (α1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J. Biol. Chem. 285, 19051–19059 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Benigni, A. et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J. Clin. Invest. 119, 524–530 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cina, D. P. et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J. Am. Soc. Nephrol. 23, 412–420 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ponticelli, C. & Graziani, G. Proteinuria after kidney transplantation. Transpl. Int. 25, 909–917 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Eid, A. A. et al. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury. Diabetes 62, 2935–2947 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Puigserver, P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-α. Int. J. Obes. (Lond.) 29 (Suppl. 1), S5–S9 (2005).

    Article  CAS  Google Scholar 

  116. Barres, R. et al. Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density. Cell. Metab. 10, 189–198 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Sharma, K. et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24, 1901–1912 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ghosh, S. et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am. J. Physiol. Renal Physiol. 296, F700–F708 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang, L. N. et al. Novel small-molecule AMP-activated protein kinase allosteric activator with beneficial effects in db/db mice. PLoS ONE 8, e72092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Avery, L. B. & Bumpus, N. N. Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice. Mol. Pharmacol. 85, 1–10 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

K.S. is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK094352), the Veterans Administration Merit Grant (5101BX000277), and the Juvenile Diabetes Research Foundation.

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Authors and Affiliations

  1. Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles (ULB), CP603, 808 Route de Lennik, Brussels, 1070, Belgium

    Anne-Emilie Declèves

  2. Center for Renal Translational Medicine, University of California, San Diego and Veterans Affairs San Diego Healthcare System, Stein Clinical Research Building, 4th Floor, 9500 Gilman Drive, La Jolla, 92093-0711, CA, USA

    Kumar Sharma

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  1. Anne-Emilie Declèves
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A.-E.D. and K.S. contributed equally to researching the data for the article, discussions of its content, writing, reviewing and editing of the manuscript before submission.

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Correspondence to Kumar Sharma.

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Competing interests

K.S. has received research funding from AbbVie, has consulted for Boerhinger-Ingelheim, Genkyotex, and Sanofi, and holds equity in Clinical Metabolomics. A.-E.D. declares no competing interests.

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Declèves, AE., Sharma, K. Novel targets of antifibrotic and anti-inflammatory treatment in CKD. Nat Rev Nephrol 10, 257–267 (2014). https://doi.org/10.1038/nrneph.2014.31

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