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Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential

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Abstract

Diabetic kidney disease, a leading cause of end-stage renal disease, has become a serious public health problem worldwide and lacks effective therapies. Autophagy is a highly conserved lysosomal degradation pathway that removes protein aggregates and damaged organelles to maintain cellular homeostasis. As important stress-responsive machinery, autophagy is involved in the pathogenesis of various diseases. Emerging evidence has suggested that dysregulated autophagy may contribute to both glomerular and tubulointerstitial pathologies in kidneys under diabetic conditions. This review summarizes the recent findings regarding the role of autophagy in the pathogenesis of diabetic kidney disease and highlights the regulation of autophagy by the nutrient-sensing pathways and intracellular stress signaling in this disease. The advances in our understanding of autophagy in diabetic kidney disease will facilitate the discovery of a new therapeutic target for the prevention and treatment of this life-threatening diabetes complication.

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References

  1. USRDS (2003) USRDS: the United States Renal Data System. Am J Kidney Dis 42(6 Suppl 5):1–230

    Google Scholar 

  2. Cao Z, Cooper ME (2011) Pathogenesis of diabetic nephropathy. J Diabetes Investig 2(4):243–247

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Shi Y, Hu FB (2014) The global implications of diabetes and cancer. Lancet 383(9933):1947–1948

    Article  PubMed  Google Scholar 

  4. Rossing P, Hougaard P, Parving HH (2005) Progression of microalbuminuria in type 1 diabetes: ten-year prospective observational study. Kidney Int 68(4):1446–1450

    Article  PubMed  Google Scholar 

  5. Ahmad J (2015) Management of diabetic nephropathy: recent progress and future perspective. Diabetes Metab Syndr 9(4):343–358

    Article  PubMed  Google Scholar 

  6. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625

    Article  CAS  PubMed  Google Scholar 

  7. Noh H, King GL (2007) The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl 106:S49–S53

    Article  CAS  Google Scholar 

  8. Calcutt NA et al (2009) Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov 8(5):417–429

    Article  CAS  PubMed  Google Scholar 

  9. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Kitada M et al (2010) Molecular mechanisms of diabetic vascular complications. J Diabetes Investig 1(3):77–89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Forbes JM, Cooper ME (2013) Mechanisms of diabetic complications. Physiol Rev 93(1):137–188

    Article  CAS  PubMed  Google Scholar 

  12. Brenner BM et al (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345(12):861–869

    Article  CAS  PubMed  Google Scholar 

  13. Lewis EJ et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345(12):851–860

    Article  CAS  PubMed  Google Scholar 

  14. Forbes JM, Fukami K, Cooper ME (2007) Diabetic nephropathy: where hemodynamics meets metabolism. Exp Clin Endocrinol Diabetes 115(2):69–84

    Article  CAS  PubMed  Google Scholar 

  15. Ruggenenti P, Cravedi P, Remuzzi G (2010) The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol 6(6):319–330

    Article  CAS  PubMed  Google Scholar 

  16. Har R et al (2013) The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Diabetologia 56(5):1166–1173

    Article  CAS  PubMed  Google Scholar 

  17. Sivitz WI, Yorek MA (2010) Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 12(4):537–577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Sharma K et al (2013) Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol 24(11):1901–1912

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Higgins GC, Coughlan MT (2014) Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br J Pharmacol 171(8):1917–1942

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Parving HH et al (1981) A prospective study of glomerular filtration rate and arterial blood pressure in insulin-dependent diabetics with diabetic nephropathy. Diabetologia 20(4):457–461

    Article  CAS  PubMed  Google Scholar 

  21. Nath KA (1992) Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20(1):1–17

    Article  CAS  PubMed  Google Scholar 

  22. Burton C, Harris KP (1996) The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis 27(6):765–775

    Article  CAS  PubMed  Google Scholar 

  23. Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17(11):2974–2984

    Article  CAS  PubMed  Google Scholar 

  24. American Diabetes A (2009) Standards of medical care in diabetes–2009. Diabetes Care 32(Suppl 1):S13–S61

    Article  Google Scholar 

  25. Yamahara K et al (2013) The role of autophagy in the pathogenesis of diabetic nephropathy. J Diabetes Res 2013:193757

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Kume S et al (2014) Autophagy: emerging therapeutic target for diabetic nephropathy. Semin Nephrol 34(1):9–16

    Article  CAS  PubMed  Google Scholar 

  27. Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146(5):682–695

    Article  CAS  PubMed  Google Scholar 

  28. Gonzalez CD et al (2011) The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 7(1):2–11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Ding Y, Choi ME (2015) Autophagy in diabetic nephropathy. J Endocrinol 224(1):R15–R30

    Article  CAS  PubMed  Google Scholar 

  30. Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741

    Article  CAS  PubMed  Google Scholar 

  32. Kuma A, Mizushima N (2010) Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol 21(7):683–690

    Article  CAS  PubMed  Google Scholar 

  33. Mizushima N, Levine B (2010) Autophagy in mammalian development and differentiation. Nat Cell Biol 12(9):823–830

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368(7):651–662

    Article  CAS  PubMed  Google Scholar 

  36. Huber TB et al (2012) Emerging role of autophagy in kidney function, diseases and aging. Autophagy 8(7):1009–1031

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Axe EL et al (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182(4):685–701

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Hayashi-Nishino M et al (2009) A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 11(12):1433–1437

    Article  CAS  PubMed  Google Scholar 

  39. Yla-Anttila P et al (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5(8):1180–1185

    Article  PubMed  Google Scholar 

  40. Hamasaki M et al (2013) Autophagosomes form at ER–mitochondria contact sites. Nature 495(7441):389–393

    Article  CAS  PubMed  Google Scholar 

  41. Lamb CA, Yoshimori T, Tooze SA (2013) The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol 14(12):759–774

    Article  CAS  PubMed  Google Scholar 

  42. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    Article  CAS  PubMed  Google Scholar 

  43. Mehrpour M et al (2010) Overview of macroautophagy regulation in mammalian cells. Cell Res 20(7):748–762

    Article  PubMed  Google Scholar 

  44. Liang C et al (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10(7):776–787

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Jager S et al (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117(Pt 20):4837–4848

    Article  PubMed  CAS  Google Scholar 

  46. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Maiuri MC et al (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8(9):741–752

    Article  CAS  PubMed  Google Scholar 

  49. Scarlatti F et al (2009) Does autophagy have a license to kill mammalian cells? Cell Death Differ 16(1):12–20

    Article  CAS  PubMed  Google Scholar 

  50. Rubinstein AD, Kimchi A (2012) Life in the balance—a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci 125(Pt 22):5259–5268

    Article  CAS  PubMed  Google Scholar 

  51. Klionsky DJ et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12(1):1–222

    Article  PubMed Central  PubMed  Google Scholar 

  52. Kume S, Thomas MC, Koya D (2012) Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes 61(1):23–29

    Article  CAS  PubMed  Google Scholar 

  53. Barbosa Junior Ade A et al (1992) Inhibition of cellular autophagy in proximal tubular cells of the kidney in streptozotocin-diabetic and uninephrectomized rats. Virchows Arch B Cell Pathol Incl Mol Pathol 61(6):359–366

    Article  PubMed  Google Scholar 

  54. Han K, Zhou H, Pfeifer U (1997) Inhibition and restimulation by insulin of cellular autophagy in distal tubular cells of the kidney in early diabetic rats. Kidney Blood Pressure Res 20(4):258–263

    Article  CAS  Google Scholar 

  55. Vallon V et al (2013) Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol 304(2):F156–F167

    Article  CAS  PubMed  Google Scholar 

  56. Kitada M et al (2011) Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp Diabetes Res 2011:908185

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  57. Yamahara K et al (2013) Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol 24(11):1769–1781

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35

    Article  CAS  PubMed  Google Scholar 

  59. Wellen KE, Thompson CB (2010) Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell 40(2):323–332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89(3):1025–1078

    Article  CAS  PubMed  Google Scholar 

  61. Imai S, Guarente L (2010) Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 31(5):212–220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Kume S et al (2014) Role of nutrient-sensing signals in the pathogenesis of diabetic nephropathy. Biomed Res Int 2014:315494

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484

    Article  CAS  PubMed  Google Scholar 

  64. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(Pt 20):3589–3594

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Inoki K (2014) mTOR signaling in autophagy regulation in the kidney. Semin Nephrol 34(1):2–8

    Article  CAS  PubMed  Google Scholar 

  66. Hosokawa N et al (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20(7):1981–1991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Jung CH et al (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20(7):1992–2003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Kim J et al (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Mori H et al (2009) The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun 384(4):471–475

    Article  CAS  PubMed  Google Scholar 

  70. Zhang MZ et al (2014) Epidermal growth factor receptor inhibition slows progression of diabetic nephropathy in association with a decrease in endoplasmic reticulum stress and an increase in autophagy. Diabetes 63(6):2063–2072

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Nagai K et al (2005) Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int 68(2):552–561

    Article  CAS  PubMed  Google Scholar 

  72. Inoki K et al (2011) mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Investig 121(6):2181–2196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Godel M et al (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Investig 121(6):2197–2209

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Velagapudi C et al (2011) The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes. J Am Soc Nephrol 22(2):262–273

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Sakaguchi M et al (2006) Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem Biophys Res Commun 340(1):296–301

    Article  CAS  PubMed  Google Scholar 

  76. Yang Y et al (2007) Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol 27(5):495–502

    Article  PubMed  CAS  Google Scholar 

  77. Wittmann S et al (2009) Long-term treatment of sirolimus but not cyclosporine ameliorates diabetic nephropathy in the rat. Transplantation 87(9):1290–1299

    Article  CAS  PubMed  Google Scholar 

  78. Lloberas N et al (2006) Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J Am Soc Nephrol 17(5):1395–1404

    Article  CAS  PubMed  Google Scholar 

  79. Stridh S et al (2015) Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan. Upsala J Med Sci 120(4):233–240

    Article  PubMed Central  PubMed  Google Scholar 

  80. Sataranatarajan K et al (2007) Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin. Am J Pathol 171(6):1733–1742

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Fang L et al (2013) Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury. PLoS One 8(4):e60546

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Xiao T et al (2014) Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice. Mol Cell Biochem 394(1–2):145–154

    Article  CAS  PubMed  Google Scholar 

  83. Kitada M et al (2016) A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. Diabetologia 59(6):1307–1317

    Article  CAS  PubMed  Google Scholar 

  84. Huber TB, Walz G, Kuehn EW (2011) mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression. Kidney Int 79(5):502–511

    Article  CAS  PubMed  Google Scholar 

  85. Lieberthal W, Levine JS (2009) The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol 20(12):2493–2502

    Article  CAS  PubMed  Google Scholar 

  86. Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Lee JW et al (2010) The association of AMPK with ULK1 regulates autophagy. PLoS One 5(11):e15394

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Alers S et al (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32(1):2–11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Lee MJ et al (2007) A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am J Physiol Renal Physiol 292(2):F617–F627

    Article  CAS  PubMed  Google Scholar 

  90. Cammisotto PG et al (2008) Control of glycogen synthase through ADIPOR1-AMPK pathway in renal distal tubules of normal and diabetic rats. Am J Physiol Renal Physiol 294(4):F881–F889

    Article  CAS  PubMed  Google Scholar 

  91. Yamazaki T et al (2009) Combination effects of enalapril and losartan on lipid peroxidation in the kidneys of KK-Ay/Ta mice. Nephron Exp Nephrol 113(2):e66–e76

    Article  CAS  PubMed  Google Scholar 

  92. Ding DF et al (2010) Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol 31(4):363–374

    Article  CAS  PubMed  Google Scholar 

  93. Sokolovska J et al (2010) Influence of metformin on GLUT1 gene and protein expression in rat streptozotocin diabetes mellitus model. Arch Physiol Biochem 116(3):137–145

    Article  CAS  PubMed  Google Scholar 

  94. Kitada M et al (2011) Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes 60(2):634–643

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Chang CC et al (2011) Resveratrol retards progression of diabetic nephropathy through modulations of oxidative stress, proinflammatory cytokines, and AMP-activated protein kinase. J Biomed Sci 18(1):47

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Kim MY et al (2013) Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. Diabetologia 56(1):204–217

    Article  CAS  PubMed  Google Scholar 

  97. Kim J et al (2012) Renal podocyte injury in a rat model of type 2 diabetes is prevented by metformin. Exp Diabetes Res 2012:210821

    PubMed Central  PubMed  Google Scholar 

  98. Dugan LL et al (2013) AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Investig 123(11):4888–4899

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Zhao L et al (2014) Berberine improves kidney function in diabetic mice via AMPK activation. PLoS One 9(11):e113398

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  100. Jin Y et al (2017) Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes. Eur J Pharmacol 794:106–114

    Article  CAS  PubMed  Google Scholar 

  101. Lee HJ et al (2012) Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells. J Biol Chem 287(7):4451–4461

    Article  CAS  PubMed  Google Scholar 

  102. Al-Rasheed NM et al (2015) Renoprotective effects of fenofibrate via modulation of LKB1/AMPK mRNA expression and endothelial dysfunction in a rat model of diabetic nephropathy. Pharmacology 95(5–6):229–239

    Article  CAS  PubMed  Google Scholar 

  103. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13(4):225–238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Chang HC, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25(3):138–145

    Article  CAS  PubMed  Google Scholar 

  105. Lee IH et al (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105(9):3374–3379

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Kume S et al (2010) Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Investig 120(4):1043–1055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Canto C et al (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458(7241):1056–1060

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Ghosh HS, McBurney M, Robbins PD (2010) SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One 5(2):e9199

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  109. He W et al (2010) Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Investig 120(4):1056–1068

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Yacoub R, Lee K, He JC (2014) The role of SIRT1 in diabetic kidney disease. Front Endocrinol (Lausanne) 5:166

    Google Scholar 

  111. Chuang PY et al (2011) Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One 6(8):e23566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Hasegawa K et al (2013) Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med 19(11):1496–1504

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Shang G et al (2013) 3,5-Diiodo-l-thyronine ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats. Biochim Biophys Acta 1832(5):674–684

    Article  CAS  PubMed  Google Scholar 

  114. Li C et al (2010) Tetrahydroxystilbene glucoside ameliorates diabetic nephropathy in rats: involvement of SIRT1 and TGF-beta1 pathway. Eur J Pharmacol 649(1–3):382–389

    Article  CAS  PubMed  Google Scholar 

  115. Wu L et al (2012) The effect of resveratrol on FoxO1 expression in kidneys of diabetic nephropathy rats. Mol Biol Rep 39(9):9085–9093

    Article  CAS  PubMed  Google Scholar 

  116. Xu Y et al (2012) Resveratrol protects against hyperglycemia-induced oxidative damage to mitochondria by activating SIRT1 in rat mesangial cells. Toxicol Appl Pharmacol 259(3):395–401

    Article  CAS  PubMed  Google Scholar 

  117. Zhang S et al (2012) SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence. Mech Ageing Dev 133(6):387–400

    Article  CAS  PubMed  Google Scholar 

  118. Ma L et al (2016) Sirt1 is essential for resveratrol enhancement of hypoxia-induced autophagy in the type 2 diabetic nephropathy rat. Pathol Res Pract 212(4):310–318

    Article  CAS  PubMed  Google Scholar 

  119. Noh H et al (2009) Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol 297(3):F729–F739

    Article  CAS  PubMed  Google Scholar 

  120. Gilbert RE et al (2011) Histone deacetylase inhibition attenuates diabetes-associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor. Kidney Int 79(12):1312–1321

    Article  CAS  PubMed  Google Scholar 

  121. Advani A et al (2011) Long-term administration of the histone deacetylase inhibitor vorinostat attenuates renal injury in experimental diabetes through an endothelial nitric oxide synthase-dependent mechanism. Am J Pathol 178(5):2205–2214

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Wang X et al (2014) Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int 86(4):712–725

    Article  CAS  PubMed  Google Scholar 

  123. Satriano J, Sharma K (2013) Autophagy and metabolic changes in obesity-related chronic kidney disease. Nephrol Dial Transplant 28(Suppl 4):iv29–iv36

    Article  PubMed Central  PubMed  Google Scholar 

  124. Sohn M et al (2017) Delayed treatment with fenofibrate protects against high-fat diet-induced kidney injury in mice: the possible role of AMPK autophagy. Am J Physiol Renal Physiol 312(2):F323–F334

    Article  CAS  PubMed  Google Scholar 

  125. Kuwahara S et al (2016) Megalin-mediated tubuloglomerular alterations in high-fat diet-induced kidney disease. J Am Soc Nephrol 27(7):1996–2008

    Article  CAS  PubMed  Google Scholar 

  126. Yamamoto T et al (2017) High-fat diet-induced lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in the kidney. J Am Soc Nephrol 28(5):1534–1551

    Article  PubMed  Google Scholar 

  127. Tagawa A et al (2016) Impaired Podocyte Autophagy Exacerbates Proteinuria in Diabetic Nephropathy. Diabetes 65(3):755–767

    Article  CAS  PubMed  Google Scholar 

  128. Bondeva T, Wolf G (2014) Reactive oxygen species in diabetic nephropathy: friend or foe? Nephrol Dial Transplant 29(11):1998–2003

    Article  CAS  PubMed  Google Scholar 

  129. Wagener FA et al (2009) The role of reactive oxygen species in apoptosis of the diabetic kidney. Apoptosis 14(12):1451–1458

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Koya D et al (2003) Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J Am Soc Nephrol 14(8 Suppl 3):S250–S253

    Article  CAS  PubMed  Google Scholar 

  131. Brezniceanu ML et al (2007) Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice. Kidney Int 71(9):912–923

    Article  CAS  PubMed  Google Scholar 

  132. Tanaka Y et al (2012) Autophagy as a therapeutic target in diabetic nephropathy. Exp Diabetes Res 2012:628978

    Article  PubMed  CAS  Google Scholar 

  133. Nishikawa T et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790

    Article  CAS  PubMed  Google Scholar 

  134. Ma T et al (2013) High glucose induces autophagy in podocytes. Exp Cell Res 319(6):779–789

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Yadav A et al (2010) ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol 299(2):C488–C496

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Jiang XS et al (2017) Autophagy protects against palmitic acid-induced apoptosis in podocytes in vitro. Sci Rep 7:42764

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Liu L et al (2008) Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. J Biol Chem 283(45):31153–31162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Sakon S et al (2003) NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22(15):3898–3909

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Cunard R (2015) Endoplasmic reticulum stress in the diabetic kidney, the good, the bad and the ugly. J Clin Med 4(4):715–740

    Article  PubMed Central  PubMed  Google Scholar 

  140. Taniguchi M, Yoshida H (2015) Endoplasmic reticulum stress in kidney function and disease. Curr Opin Nephrol Hypertens 24(4):345–350

    Article  CAS  PubMed  Google Scholar 

  141. Sieber J et al (2010) Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids. Am J Physiol Renal Physiol 299(4):F821–F829

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Cao Y et al (2014) Role of endoplasmic reticulum stress in apoptosis of differentiated mouse podocytes induced by high glucose. Int J Mol Med 33(4):809–816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Cybulsky AV (2010) Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int 77(3):187–193

    Article  CAS  PubMed  Google Scholar 

  144. Lindenmeyer MT et al (2008) Proteinuria and hyperglycemia induce endoplasmic reticulum stress. J Am Soc Nephrol 19(11):2225–2236

    Article  PubMed Central  PubMed  Google Scholar 

  145. Ohse T et al (2006) Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells. Kidney Int 70(8):1447–1455

    Article  CAS  PubMed  Google Scholar 

  146. Wu J et al (2010) Induction of diabetes in aged C57B6 mice results in severe nephropathy: an association with oxidative stress, endoplasmic reticulum stress, and inflammation. Am J Pathol 176(5):2163–2176

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Rouschop KM et al (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Investig 120(1):127–141

    Article  CAS  PubMed  Google Scholar 

  148. Ogata M et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Chen Y et al (2008) Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes. Am J Nephrol 28(6):1014–1022

    Article  CAS  PubMed  Google Scholar 

  150. Cao A et al (2016) Ursodeoxycholic acid ameliorated diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress. Biol Pharm Bull 39(8):1300–1308

    Article  CAS  PubMed  Google Scholar 

  151. Qi W et al (2011) Attenuation of diabetic nephropathy in diabetes rats induced by streptozotocin by regulating the endoplasmic reticulum stress inflammatory response. Metab Clin Exp 60(5):594–603

    Article  CAS  PubMed  Google Scholar 

  152. Luo ZF et al (2010) Effects of 4-phenylbutyric acid on the process and development of diabetic nephropathy induced in rats by streptozotocin: regulation of endoplasmic reticulum stress-oxidative activation. Toxicol Appl Pharmacol 246(1–2):49–57

    Article  CAS  PubMed  Google Scholar 

  153. Cao AL et al (2016) Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy. Lab Investig 96(6):610–622

    Article  CAS  PubMed  Google Scholar 

  154. Wenger RH (2002) Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 16(10):1151–1162

    Article  CAS  PubMed  Google Scholar 

  155. Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5(5):343–354

    Article  CAS  PubMed  Google Scholar 

  156. Haase VH (2006) Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol 291(2):F271–F281

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Mazure NM, Pouyssegur J (2010) Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol 22(2):177–180

    Article  CAS  PubMed  Google Scholar 

  158. Rouschop KM, Wouters BG (2009) Regulation of autophagy through multiple independent hypoxic signaling pathways. Curr Mol Med 9(4):417–424

    Article  CAS  PubMed  Google Scholar 

  159. Tracy K et al (2007) BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 27(17):6229–6242

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Zhang H et al (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283(16):10892–10903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Bellot G et al (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29(10):2570–2581

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  162. Pagtalunan ME et al (1997) Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Investig 99(2):342–348

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  163. Wolf G, Chen S, Ziyadeh FN (2005) From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54(6):1626–1634

    Article  CAS  PubMed  Google Scholar 

  164. Meyer TW, Bennett PH, Nelson RG (1999) Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 42(11):1341–1344

    Article  CAS  PubMed  Google Scholar 

  165. Hartleben B et al (2010) Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Investig 120(4):1084–1096

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  166. Mizushima N et al (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15(3):1101–1111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Sato S et al (2006) Two types of autophagy in the podocytes in renal biopsy specimens: ultrastructural study. J Submicrosc Cytol Pathol 38(2–3):167–174

    CAS  PubMed  Google Scholar 

  168. Chen J et al (2013) mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J Am Soc Nephrol 24(2):198–207

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  169. Cina DP et al (2012) Inhibition of MTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol 23(3):412–420

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  170. Oshima Y et al (2011) Prorenin receptor is essential for normal podocyte structure and function. J Am Soc Nephrol 22(12):2203–2212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Lenoir O et al (2015) Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11(7):1130–1145

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Liu J et al (2016) beta-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy. Cell Death Dis 7:e2183

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Sun J et al (2017) Repression of miR-217 protects against high glucose-induced podocyte injury and insulin resistance by restoring PTEN-mediated autophagy pathway. Biochem Biophys Res Commun 483(1):318–324

    Article  CAS  PubMed  Google Scholar 

  174. Li W et al (2017) FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/Parkin pathway. Endocrinology. doi:10.1210/en.2016-1970

    Google Scholar 

  175. Liu S et al (2012) Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8(5):826–837

    Article  CAS  PubMed  Google Scholar 

  176. Kimura T et al (2011) Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol 22(5):902–913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Livingston MJ, Dong Z (2014) Autophagy in acute kidney injury. Semin Nephrol 34(1):17–26

    Article  CAS  PubMed  Google Scholar 

  178. Havasi A, Dong Z (2016) Autophagy and tubular cell death in the kidney. Semin Nephrol 36(3):174–188

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  179. Nair S, Wilding JP (2010) Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 95(1):34–42

    Article  CAS  PubMed  Google Scholar 

  180. Huang C et al (2016) Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway. Sci Rep 6:29196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  181. Saito A et al (2005) Significance of proximal tubular metabolism of advanced glycation end products in kidney diseases. Ann N Y Acad Sci 1043:637–643

    Article  CAS  PubMed  Google Scholar 

  182. Liu WJ et al (2015) Autophagy-lysosome pathway in renal tubular epithelial cells is disrupted by advanced glycation end products in diabetic nephropathy. J Biol Chem 290(33):20499–20510

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  183. Takahashi A et al (2017) Autophagy inhibits the accumulation of advanced glycation end products by promoting lysosomal biogenesis and function in the kidney proximal tubules. Diabetes 66(5):1359–1372

    Article  CAS  PubMed  Google Scholar 

  184. Fiorentino L et al (2013) Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol Med 5(3):441–455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  185. Xu L et al (2016) Inhibition of autophagy increased AGE/ROS-mediated apoptosis in mesangial cells. Cell Death Dis 7(11):e2445

    Article  PubMed Central  PubMed  Google Scholar 

  186. Lu X et al (2015) Ursolic acid attenuates diabetic mesangial cell injury through the up-regulation of autophagy via miRNA-21/PTEN/Akt/mTOR suppression. PLoS One 10(2):e0117400

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  187. Xavier S et al (2010) BAMBI is expressed in endothelial cells and is regulated by lysosomal/autolysosomal degradation. PLoS One 5(9):e12995

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  188. Fan Y et al (2015) BAMBI elimination enhances alternative TGF-beta signaling and glomerular dysfunction in diabetic mice. Diabetes 64(6):2220–2233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7(12):684–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  190. Li L et al (2010) Autophagy is a component of epithelial cell fate in obstructive uropathy. Am J Pathol 176(4):1767–1778

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. Forbes MS, Thornhill BA, Chevalier RL (2011) Proximal tubular injury and rapid formation of atubular glomeruli in mice with unilateral ureteral obstruction: a new look at an old model. Am J Physiol Renal Physiol 301(1):F110–F117

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  192. Xu Y et al (2013) Autophagy and apoptosis in tubular cells following unilateral ureteral obstruction are associated with mitochondrial oxidative stress. Int J Mol Med 31(3):628–636

    Article  CAS  PubMed  Google Scholar 

  193. Koesters R et al (2010) Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol 177(2):632–643

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Livingston MJ et al (2016) Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy 12(6):976–998

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  195. Baisantry A et al (2016) Autophagy induces prosenescent changes in proximal tubular S3 segments. J Am Soc Nephrol 27(6):1609–1616

    Article  CAS  PubMed  Google Scholar 

  196. Kim WY et al (2012) The role of autophagy in unilateral ureteral obstruction rat model. Nephrology 17(2):148–159

    Article  CAS  PubMed  Google Scholar 

  197. Kim SI et al (2012) Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J Biol Chem 287(15):11677–11688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  198. Ding Y et al (2014) Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J Am Soc Nephrol 25(12):2835–2846

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  199. Colman RJ et al (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325(5937):201–204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  200. Fontana L, Partridge L, Longo VD (2010) Extending healthy life span—from yeast to humans. Science 328(5976):321–326

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

This study was supported by grants from National Natural Science Foundation of China (81528004, 81370791), the National Institutes of Health and Department of Veterans Administration of USA.

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  1. Danyi Yang and Man J. Livingston are co-first authors.

Authors and Affiliations

  1. Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China

    Danyi Yang, Zhiwen Liu & Zheng Dong

  2. Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd, Augusta, GA, 30912, USA

    Man J. Livingston, Guie Dong, Ming Zhang, Jian-Kang Chen & Zheng Dong

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  1. Danyi Yang
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  2. Man J. Livingston
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  3. Zhiwen Liu
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  4. Guie Dong
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  5. Ming Zhang
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Correspondence to Zheng Dong.

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Yang, D., Livingston, M.J., Liu, Z. et al. Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell. Mol. Life Sci. 75, 669–688 (2018). https://doi.org/10.1007/s00018-017-2639-1

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  • DOI: https://doi.org/10.1007/s00018-017-2639-1

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