Diabetes Metab J.  2015 Dec;39(6):451-460. 10.4093/dmj.2015.39.6.451.

Autophagy: A Novel Therapeutic Target for Diabetic Nephropathy

• Kume S
• Koya D

• KMID: 2173996
• DOI: http://doi.org/10.4093/dmj.2015.39.6.451

Abstract

Diabetic nephropathy is a leading cause of end stage renal disease and its occurance is increasing worldwide. The most effective treatment strategy for the condition is intensive treatment to strictly control glycemia and blood pressure using renin-angiotensin system inhibitors. However, a fraction of patients still go on to reach end stage renal disease even under such intensive care. New therapeutic targets for diabetic nephropathy are, therefore, urgently needed. Autophagy is a major catabolic pathway by which mammalian cells degrade macromolecules and organelles to maintain intracellular homeostasis. The accumulation of damaged proteins and organelles is associated with the pathogenesis of diabetic nephropathy. Autophagy in the kidney is activated under some stress conditions, such as oxidative stress and hypoxia in proximal tubular cells, and occurs even under normal conditions in podocytes. These and other accumulating findings have led to a hypothesis that autophagy is involved in the pathogenesis of diabetic nephropathy. Here, we review recent findings underpinning this hypothesis and discuss the advantages of targeting autophagy for the treatment of diabetic nephropathy.

Keyword

AMP-activated protein kinases; Autophagy; Caloric restriction; Diabetic nephropathy; Mechanistic target of rapamycin complex 1; Podocytes; Sirt1; Tubular cell

MeSH Terms

AMP-Activated Protein Kinases
Anoxia
Autophagy*
Blood Pressure
Caloric Restriction
Diabetic Nephropathies*
Homeostasis
Humans
Critical Care
Kidney
Kidney Failure, Chronic
Organelles
Oxidative Stress
Podocytes
Renin-Angiotensin System
AMP-Activated Protein Kinases

Figure

• 

  Fig. 1 Nutrient regulation of autophagy. Autohagosome formation is regulated by a number of autophagy-related proteins at multiple steps. Initiation of autophagy via Ulk1 complex is negatively and positively regulated by mammalian target of rapamycin complex 1 (mTORC1)- and 5'-AMP-activated protein kinase (AMPK)-dependent phosphorylation, respectively. Sirt1-dependent deacetylation is also involved in the activation of autophagy. Origin of autophagosome membrane is endoplasmic reticulum (ER) membrane. Autophagosome fuses with lysosome to form autolysosome and is finally degraded by lysosome enzymes. NAD, nicotinamide adenine dinucleotide; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Atg, autophagy-related gene; LC3, light chain 3; Ulk1, unc-51-like kinase 1; PE, phosphatidylethanolamine; FOXO3a, forkhead box O3a.

• 

  Fig. 2 Autophagy activity determined using green fluorescent protein light chain 3 (GFP-LC3) transgenic mouse. Autopphagome can be detected as GFP-LC3 dots in tissues of this mouse model. Autophagosomes formation is constitutively observed in podocytes even under ad-libitum condition. In contrast, autophagy can be observed in proximal tubular cells exposed to 48-hour fasting. The white dotted line box indicates the area for each enlarged figure. Blue signal, DAPI stain to visualize nuclei. Red signal, nidogen stain to visualize basement membrane. Green signal, GFP signal indicating LC3 protein.

• 

  Fig. 3 Podocytes and proximal tubular cells have basal and stress-responsive autophagy, which is essential to maintain cellular homeostasis. Some pathological situations such as diabetes, obesity, and aging suppresses both basal and stress-responsive autophagy, leading to massive proteinuria and severe tubular cell damage.

Reference

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

2. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54:1615–1625.

3. Dunlop M. Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl. 2000; 77:S3–S12.

4. Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, Cooper ME. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 2003; 17:1762–1764.

5. Ha H, Hwang IA, Park JH, Lee HB. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract. 2008; 82:Suppl 1. S42–S45.

6. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998; 47:859–866.

7. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S;. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861–869.

8. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977–986.

9. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837–853.

10. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995; 28:103–117.

11. Araki S, Haneda M, Sugimoto T, Isono M, Isshiki K, Kashiwagi A, Koya D. Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes. Diabetes. 2005; 54:2983–2987.

12. Yokoyama H, Araki S, Honjo J, Okizaki S, Yamada D, Shudo R, Shimizu H, Sone H, Moriya T, Haneda M. Association between remission of macroalbuminuria and preservation of renal function in patients with type 2 diabetes with overt proteinuria. Diabetes Care. 2013; 36:3227–3233.

13. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007; 8:519–529.

14. Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010; 40:280–293.

15. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature. 2009; 458:1131–1135.

16. Yoshizaki T, Kusunoki C, Kondo M, Yasuda M, Kume S, Morino K, Sekine O, Ugi S, Uzu T, Nishio Y, Kashiwagi A, Maegawa H. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun. 2012; 417:352–357.

17. Huber TB, Edelstein CL, Hartleben B, Inoki K, Jiang M, Koya D, Kume S, Lieberthal W, Pallet N, Quiroga A, Ravichandran K, Susztak K, Yoshida S, Dong Z. Emerging role of autophagy in kidney function, diseases and aging. Autophagy. 2012; 8:1009–1031.

18. Hartleben B, Godel M, Meyer-Schwesinger C, Liu S, Ulrich T, Kobler S, Wiech T, Grahammer F, Arnold SJ, Lindenmeyer MT, Cohen CD, Pavenstadt H, Kerjaschki D, Mizushima N, Shaw AS, Walz G, Huber TB. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010; 120:1084–1096.

19. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, Sugimoto T, Haneda M, Kashiwagi A, Koya D. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest. 2010; 120:1043–1055.

20. Kume S, Thomas MC, Koya D. Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes. 2012; 61:23–29.

21. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011; 147:728–741.

22. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature. 2004; 432:1032–1036.

23. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999; 402:672–676.

24. Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie. 2008; 90:313–323.

25. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007; 131:1149–1163.

26. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009; 20:1981–1991.

27. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011; 13:1016–1023.

28. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011; 13:132–141.

29. Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005; 6:298–305.

30. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008; 105:3374–3379.

31. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004; 15:1101–1111.

32. Kawachi H, Miyauchi N, Suzuki K, Han GD, Orikasa M, Shimizu F. Role of podocyte slit diaphragm as a filtration barrier. Nephrology (Carlton). 2006; 11:274–281.

33. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997; 99:342–348.

34. Chen J, Chen MX, Fogo AB, Harris RC, Chen JK. mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J Am Soc Nephrol. 2013; 24:198–207.

35. Cina DP, Onay T, Paltoo A, Li C, Maezawa Y, De Arteaga J, Jurisicova A, Quaggin SE. Inhibition of MTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol. 2012; 23:412–420.

36. Oshima Y, Kinouchi K, Ichihara A, Sakoda M, Kurauchi-Mito A, Bokuda K, Narita T, Kurosawa H, Sun-Wada GH, Wada Y, Yamada T, Takemoto M, Saleem MA, Quaggin SE, Itoh H. Prorenin receptor is essential for normal podocyte structure and function. J Am Soc Nephrol. 2011; 22:2203–2212.

37. Fang L, Zhou Y, Cao H, Wen P, Jiang L, He W, Dai C, Yang J. Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury. PLoS One. 2013; 8:e60546.

38. Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M, Araki H, Araki SI, Koya D, Asanuma K, Kim EH, Haneda M, Kajiwara N, Hayashi K, Ohashi H, Ugi S, Maegawa H, Uzu T. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes. 2015; 09. 17. [Epub]. DOI: 10.2337/db15-0473.

39. Lenoir O, Jasiek M, Henique C, Guyonnet L, Hartleben B, Bork T, Chipont A, Flosseau K, Bensaada I, Schmitt A, Masse JM, Souyri M, Huber TB, Tharaux PL. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy. 2015; 11:1130–1145.

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

41. Risdon RA, Sloper JC, De Wardener HE. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet. 1968; 2:363–366.

42. Mallamaci F, Ruggenenti P, Perna A, Leonardis D, Tripepi R, Tripepi G, Remuzzi G, Zoccali C. ACE inhibition is renoprotective among obese patients with proteinuria. ACE inhibition is renoprotective among obese patients with proteinuria. J Am Soc Nephrol. 2011; 22:1122–1128.

43. Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I, Namba T, Kitamura H, Niimura F, Matsusaka T, Soga T, Rakugi H, Isaka Y. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol. 2011; 22:902–913.

44. Liu S, Hartleben B, Kretz O, Wiech T, Igarashi P, Mizushima N, Walz G, Huber TB. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy. 2012; 8:826–837.

45. Yang C, Kaushal V, Shah SV, Kaushal GP. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol Renal Physiol. 2008; 294:F777–F787.

46. Takahashi A, Kimura T, Takabatake Y, Namba T, Kaimori J, Kitamura H, Matsui I, Niimura F, Matsusaka T, Fujita N, Yoshimori T, Isaka Y, Rakugi H. Autophagy guards against cisplatin-induced acute kidney injury. Am J Pathol. 2012; 180:517–525.

47. Yamahara K, Kume S, Koya D, Tanaka Y, Morita Y, Chin-Kanasaki M, Araki H, Isshiki K, Araki S, Haneda M, Matsusaka T, Kashiwagi A, Maegawa H, Uzu T. Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol. 2013; 24:1769–1781.

48. Kitada M, Takeda A, Nagai T, Ito H, Kanasaki K, Koya D. 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; 2011:908185.

49. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009; 325:201–204.

50. Fontana L, Partridge L, Longo VD. Extending healthy life span: from yeast to humans. Science. 2010; 328:321–326.

51. Cherry , Engelman RW, Wang BY, Kinjoh K, El-Badri NS, Good RA. Calorie restriction delays the crescentic glomerulonephritis of SCG/Kj mice. Proc Soc Exp Biol Med. 1998; 218:218–222.

52. Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, Blattner SM, Ikenoue T, Ruegg MA, Hall MN, Kwiatkowski DJ, Rastaldi MP, Huber TB, Kretzler M, Holzman LB, Wiggins RC, Guan KL. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011; 121:2181–2196.

53. Kume S, Uzu T, Araki S, Sugimoto T, Isshiki K, Chin-Kanasaki M, Sakaguchi M, Kubota N, Terauchi Y, Kadowaki T, Haneda M, Kashiwagi A, Koya D. Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol. 2007; 18:2715–2723.

54. Chang CC, Chang CY, Wu YT, Huang JP, Yen TH, Hung LM. Resveratrol retards progression of diabetic nephropathy through modulations of oxidative stress, proinflammatory cytokines, and AMP-activated protein kinase. J Biomed Sci. 2011; 18:47.

55. Takiyama Y, Harumi T, Watanabe J, Fujita Y, Honjo J, Shimizu N, Makino Y, Haneda M. Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism. Diabetes. 2011; 60:981–992.

56. Ding DF, You N, Wu XM, Xu JR, Hu AP, Ye XL, Zhu Q, Jiang XQ, Miao H, Liu C, Lu YB. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol. 2010; 31:363–374.

57. Lee MJ, Feliers D, Mariappan MM, Sataranatarajan K, Mahimainathan L, Musi N, Foretz M, Viollet B, Weinberg JM, Choudhury GG, Kasinath BS. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am J Physiol Renal Physiol. 2007; 292:F617–F627.

58. Hasegawa K, Wakino S, Simic P, Sakamaki Y, Minakuchi H, Fujimura K, Hosoya K, Komatsu M, Kaneko Y, Kanda T, Kubota E, Tokuyama H, Hayashi K, Guarente L, Itoh H. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med. 2013; 19:1496–1504.