Novel targets of antifibrotic and anti-inflammatory treatment in CKD

Nature Reviews Nephrology

Volumn 10, Issue 5, 2014, Pages 257-267

  Declèves, Anne Emilie ^a   Sharma, Kumar ^b,c  

^a UNIVERSITÉ LIBRE DE BRUXELLES   (Belgium)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c VA SAN DIEGO HEALTHCARE SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADVANCED GLYCATION END PRODUCT; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIFIBROTIC AGENT; ANTIINFLAMMATORY AGENT; CELASTROL; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; FG 3019; FIBROBLAST GROWTH FACTOR 23; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; OSTEOGENIC PROTEIN 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIRFENIDONE; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 1; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; SIRTUIN; SORBITOL; SUPEROXIDE; TRANILAST; TRANSFORMING GROWTH FACTOR BETA;

ARTICLE; BLOOD VESSEL CALCIFICATION; CELL DEDIFFERENTIATION; CELL PROLIFERATION; CHRONIC KIDNEY DISEASE; DIABETIC NEPHROPATHY; DISEASE ASSOCIATION; ENZYME ACTIVATION; EXTRACELLULAR MATRIX; GLOMERULOSCLEROSIS; HUMAN; HYPERPHOSPHATEMIA; INSULIN DEPENDENT DIABETES MELLITUS; KIDNEY FIBROSIS; KIDNEY TUBULE CELL; MITOCHONDRIAL ENERGY TRANSFER; MYOFIBROBLAST; NEPHRITIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PODOCYTE; PRIORITY JOURNAL; PROTEIN FUNCTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; SOFT TISSUE CALCIFICATION; TREATMENT OUTCOME; UPREGULATION; VASCULAR SMOOTH MUSCLE;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; ANTI-INFLAMMATORY AGENTS; DIABETES MELLITUS, TYPE 1; DIABETES MELLITUS, TYPE 2; DISEASE PROGRESSION; FIBROBLAST GROWTH FACTORS; FIBROSIS; GLUCURONIDASE; HUMANS; MITOCHONDRIA; MODELS, ANIMAL; NADPH OXIDASE; NF-KAPPA B; RENAL INSUFFICIENCY, CHRONIC; TRANSFORMING GROWTH FACTOR BETA; VASCULAR CALCIFICATION;

EID: 85047689437     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2014.31     Document Type: Article

References (120)

1. Jha, V. et al. Chronic kidney disease: global dimension and perspectives. Lancet 382, 260-272 (2013).
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], http://www.reportlinker.com/ p01887614/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.html (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).
4. Chen, S. et al. Reversibility of established diabetic glomerulopathy by anti-TGF-β antibodies n db/db mice. Biochem. Biophys. Res. Commun. 300, 16-22 (2003).
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).
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).
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).
8. Negri, A. L. Prevention of progressive fibrosis in chronic renal diseases: antifibrotic agents. J. Nephrol. 17, 496-503 (2004).
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).
10. Liu, Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 69, 213-217 (2006).
11. Border, W. A. & Noble, N. A. Transforming growth factor β in tissue fibrosis. N. Engl. J. Med. 331, 1286-1292 (1994).
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).
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).
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).
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).
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).
17. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01113801 (2013).
18. Boor, P. & Floege, J. Chronic kidney disease growth factors in renal fibrosis. Clin. Exp. Pharmacol. Physiol. 38, 441-450 (2011).
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).
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).
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).
22. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00754143 (2011).
23. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00913393 (2012).
24. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00782561 (2009).
25. Ramachandrarao, S. P. et al. Pirfenidone is renoprotective in diabetic kidney disease. J. Am. Soc. Nephrol. 20, 1765-1775 (2009).
26. Chen, J. F. et al. Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats. Am. J. Physiol. Renal Physiol. 304, F676-F685 (2013).
27. Sharma, K. et al. Pirfenidone for diabetic nephropathy. J. Am. Soc. Nephrol. 22, 1144-1151 (2011).
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).
29. Tao, Y. et al. Tranilast attenuates chronic cyclosporine nephrotoxicity in rats. Transplant. Proc. 41, 4373-4375 (2009).
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).
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).
32. Soma, J., Sato, K., Saito, H. & Tsuchiya, Y. Effect of tranilast in early-stage diabetic nephropathy. Nephrol. Dial. Transplant. 21, 2795-2799 (2006).
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).
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).
35. Gilbert, R. E. et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS ONE 7, e47160 (2012).
36. Australian New Zealand Clinical Trials Registry. Anzctr.org [online], https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN= 12613000386730 (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).
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).
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).
40. Putta, S. et al. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J. A m. Soc. Nephrol. 23, 458-469 (2012).
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).
42. Spanjol, J. et al. Bone morphogenetic protein-7 expression in human pyelonephritis. Coll. Antropol. 34 (Suppl. 2), 61-64 (2010).
43. Bramlage, C. P. et al. Bone morphogenetic protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis. BMC Nephrol. 11, 31 (2010).
44. Zeisberg, M. et al. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964-968 (2003).
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).
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).
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).
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).
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).
50. Wang, H. Y. et al. Hepatocyte growth factor-nduced amelioration in chronic renal failure is associated with reduced expression of a-smooth muscle actin. Ren. Fail. 34, 862-870 (2012).
51. Okada, H. et al. Transgene-derived hepatocyte growth factor attenuates reactive renal fibrosis n aristolochic acid nephrotoxicity. Nephrol. Dial. Transplant. 18, 2515-2523 (2003).
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).
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).
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).
55. Chai, Z. et al. Genetic deletion of cell division autoantigen 1 retards diabetes-associated renal njury. J. Am. Soc. Nephrol. 24, 1782-1792 (2013).
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).
57. Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. 121, 4393-4408 (2011).
58. Komaba, H. & Fukagawa, M. The role of FGF23 n CKD-with or without Klotho. Nat Rev. Nephrol. 8, 484-490 (2012).
59. Hu, M. C, Kuro-o, M. & Moe, O. W. Klotho and kidney disease. J. Nephrol. 23 (Suppl. 16), S136-S144 (2010).
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).
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).
62. Hu, M. C. et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 22, 124-136 (2011).
63. Fischer, S. S. et al. Hyperaldosteronism in Klotho-deficient mice. Am. J. Physiol. Renal Physiol. 299, F1171-F1177 (2010).
64. Voelkl, J. et al. Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. J. Clin. Invest. 123, 812-822 (2013).
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).
66. Sanz-Rosa, D. et al. Participation of aldosterone n the vascular inflammatory response of spontaneously hypertensive rats: role of the NFKB/IKB system. J. Hypertens. 23, 1167-1172 (2005).
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).
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).
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).
70. Coughlan, M. T. et al. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J. Am. Soc. Nephrol. 20, 742-752 (2009).
71. Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615-1625 (2005).
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).
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).
74. You, Y. H. et al. Role of Nox2 in diabetic kidney disease. Am. J. Physiol. Renal Physiol. 304, F840-F848 (2013).
75. Sharma, K. et al. Adiponectin regulates albuminuria and podocyte function in mice. J. Clin. Invest. 118, 1645-1656 (2008).
76. Babelova, A. et al. Role of Nox4 in murine models of kidney disease. Free Radic. Biol. Med. 53, 842-853 (2012).
77. Gorin, Y. & Block, K. Nox as a target for diabetic complications. Clin. Sci. (Lond.) 125, 361-382 (2013).
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).
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).
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).
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).
83. Gray, S. P. et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation 127, 1888-1902 (2013).
84. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT02010242 (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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
95. Goumenos, D. S. et al. Early histological changes in the kidney of people with morbid obesity. Nephrol. Dial. Transplant. 24, 3732-3738 (2009).
96. Chagnac, A. et al. Glomerular hemodynamics in severe obesity. Am. J. Physiol. Renal Physiol. 278, F817-F822 (2000).
97. Kershaw, E. E. & Flier, J. S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89, 2548-2556 (2004).
98. Ruster, C. & Wolf, G. The role of the renin-angiotensin-aldosterone system in obesity-related renal diseases. Semin. Nephrol. 33, 44-53 (2013).
99. Ruster, C. & Wolf, G. Adipokines promote chronic kidney disease. Nephrol. Dial. Transplant. 28 (Suppl. 4), iv8-iv14 (2013).
100. O'Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346-355 (2013).
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).
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).
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).
105. Dugan, L. L. et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest. 123, 4888-4899 (2013).
106. Mishra, R. et al. AMP-activated protein kinase nhibits transforming growth factor-β-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J. Biol. Chem. 283, 10461-10469 (2008).
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).
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).
109. Yang, Z., Kahn, B. B., Shi, H. & Xue, B. Z. Macrophage a1 AMP-activated protein kinase (a1AMPK) antagonizes fatty acid-induced nflammation through SIRT1. J. Biol. Chem. 285, 19051-19059 (2010).
110. Benigni, A. et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J. Clin. Invest. 119, 524-530 (2009).
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).
112. Cina, D. P. et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J. Am. Soc. Nephrol. 23, 412-420 (2012).
113. Ponticelli, C. & Graziani, G. Proteinuria after kidney transplantation. Transpl. Int. 25, 909-917 (2012).
114. Eid, A. A. et al. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury. Diabetes 62, 2935-2947 (2013).
115. Puigserver, P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-a. Int J. Obes. (Lond.) 29 (Suppl. 1), S5-S9 (2005).
116. Barres, R. et al. Non-CpG methylation of the PGC-1a promoter through DNMT3B controls mitochondrial density. Cell. Metab. 10, 189-198 (2009).
117. Sharma, K. et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24, 1901-1912 (2013).
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).
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).
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).