Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to combat diabetic nephropathy is required. Autophagy is a catabolic process that degrades damaged proteins and organelles in mammalian cells and plays a critical role in maintaining cellular homeostasis. The accumulation of proteins and organelles damaged by hyperglycemia and other diabetes-related metabolic changes is highly associated with the development of diabetic nephropathy. Recent studies have suggested that autophagy activity is altered in both podocytes and proximal tubular cells under diabetic conditions. Autophagy activity is regulated by both nutrient state and intracellular stresses. Under diabetic conditions, an altered nutritional state due to nutrient excess may interfere with the autophagic response stimulated by intracellular stresses, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing the relationships between autophagy and diabetic nephropathy and suggest the therapeutic potential of autophagy in diabetic nephropathy. 1. Introduction The increasing prevalence of diabetes mellitus and its vascular complications has become a major health problem worldwide. Diabetic nephropathy is a serious complication of diabetes and is a common cause of end-stage renal disease. Diabetes induces glomerular damage, along with proteinuria, and subsequent tubulointerstitial lesions, leading to end-stage renal disease [1–3]. Initially, the patient shows hyperfiltration, represented by high glomerular filtration rates (GFRs) and occasional occurrence of microalbuminuria. Later, the patient shows a gradual decline in the GFR and persistence of microalbuminuria that comes before mild and subsequently moderate proteinuria. Urinary protein seems to be almost entirely reabsorbed in early and late proximal tubules and may induce tubulointerstitial damage [3]. Reducing proteinuria by keeping blood pressure and blood glucose levels under control is therefore a primary therapeutic goal with diabetic nephropathy [4, 5]. Unfortunately, however, some patients develop treatment-resistant proteinuria, resulting in end-stage renal disease. There is now an urgent need to identify new therapeutic target molecules or cellular processes that underlie the pathogenesis of diabetic nephropathy to establish additional
References
[1]
C. Burton and K. P. G. Harris, “The role of proteinuria in the progression of chronic renal failure,” American Journal of Kidney Diseases, vol. 27, no. 6, pp. 765–775, 1996.
[2]
M. Abbate, C. Zoja, and G. Remuzzi, “How does proteinuria cause progressive renal damage?” Journal of the American Society of Nephrology, vol. 17, no. 11, pp. 2974–2984, 2006.
[3]
K. A. Nath, “Tubulointerstitial changes as a major determinant in the progression of renal damage,” American Journal of Kidney Diseases, vol. 20, no. 1, pp. 1–17, 1992.
[4]
J. C. Peterson, S. Adler, J. M. Burkart et al., “Blood pressure control, proteinuria, and the progression of renal disease: the modification of diet in renal disease study,” Annals of Internal Medicine, vol. 123, no. 10, pp. 754–762, 1995.
[5]
B. M. Brenner, M. E. Cooper, D. De Zeeuw et al., “Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy,” The New England Journal of Medicine, vol. 345, no. 12, pp. 861–869, 2001.
[6]
D. C. Rubinsztein, G. Mari？o, and G. Kroemer, “Autophagy and aging,” Cell, vol. 146, no. 5, pp. 682–695, 2011.
[7]
C. D. Gonzalez, M.-S. Lee, P. Marchetti et al., “The emerging role of autophagy in the pathophysiology of diabetes mellitus,” Autophagy, vol. 7, no. 1, pp. 2–11, 2011.
[8]
N. Mizushima, B. Levine, A. M. Cuervo, and D. J. Klionsky, “Autophagy fights disease through cellular self-digestion,” Nature, vol. 451, no. 7182, pp. 1069–1075, 2008.
[9]
B. Hartleben, M. G？del, C. Meyer-Schwesinger et al., “Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1084–1096, 2010.
[10]
S. Kume, T. Uzu, K. Horiike et al., “Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1043–1055, 2010.
[11]
T. Kimura, Y. Takabatake, A. Takahashi et al., “Autophagy protects the proximal tubule from degeneration and acute ischemic injury,” Journal of the American Society of Nephrology, vol. 22, no. 5, pp. 902–913, 2011.
[12]
M. Jiang, K. Liu, J. Luo, and Z. Dong, “Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury,” American Journal of Pathology, vol. 176, no. 3, pp. 1181–1192, 2010.
[13]
A. Takahashi, T. Kimura, Y. Takabatake et al., “Autophagy guards against cisplatin-induced acute kidney injury,” American Journal of Pathology, vol. 180, no. 2, pp. 517–525, 2012.
[14]
S. Periyasamy-Thandavan, M. Jiang, Q. Wei, R. Smith, X.-M. Yin, and Z. Dong, “Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells,” Kidney International, vol. 74, no. 5, pp. 631–640, 2008.
[15]
C. Yang, V. Kaushal, S. V. Shah, and G. P. Kaushal, “Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells,” American Journal of Physiology—Renal Physiology, vol. 294, no. 4, pp. F777–F787, 2008.
[16]
D. J. Klionsky, “The molecular machinery of autophagy: unanswered questions,” Journal of Cell Science, vol. 118, no. 1, pp. 7–18, 2005.
[17]
A. C. Massey, C. Zhang, and A. M. Cuervo, “Chaperone-mediated autophagy in aging and disease,” Current Topics in Developmental Biology, vol. 73, pp. 205–235, 2006.
[18]
S. A. Tooze and T. Yoshimori, “The origin of the autophagosomal membrane,” Nature Cell Biology, vol. 12, no. 9, pp. 831–835, 2010.
[19]
I. G. Ganley, D. H. Lam, J. Wang, X. Ding, S. Chen, and X. Jiang, “ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy,” The Journal of Biological Chemistry, vol. 284, no. 18, pp. 12297–12305, 2009.
[20]
N. Hosokawa, T. Hara, T. Kaizuka et al., “Nutrient-dependent mTORCl association with the ULK1-Atg13-FIP200 complex required for autophagy,” Molecular Biology of the Cell, vol. 20, no. 7, pp. 1981–1991, 2009.
[21]
C. H. Jung, C. B. Jun, S.-H. Ro et al., “ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery,” Molecular Biology of the Cell, vol. 20, no. 7, pp. 1992–2003, 2009.
[22]
X. H. Liang, S. Jackson, M. Seaman et al., “Induction of autophagy and inhibition of tumorigenesis by beclin 1,” Nature, vol. 402, no. 6762, pp. 672–676, 1999.
[23]
S. Pattingre, L. Espert, M. Biard-Piechaczyk, and P. Codogno, “Regulation of macroautophagy by mTOR and Beclin 1 complexes,” Biochimie, vol. 90, no. 2, pp. 313–323, 2008.
[24]
H. Nakatogawa, K. Suzuki, Y. Kamada, and Y. Ohsumi, “Dynamics and diversity in autophagy mechanisms: lessons from yeast,” Nature Reviews Molecular Cell Biology, vol. 10, no. 7, pp. 458–467, 2009.
[25]
B. Ravikumar, S. Sarkar, J. E. Davies et al., “Regulation of mammalian autophagy in physiology and pathophysiology,” Physiological Reviews, vol. 90, no. 4, pp. 1383–1435, 2010.
[26]
N. Mizushima, T. Yoshimori, and B. Levine, “Methods in mammalian autophagy research,” Cell, vol. 140, no. 3, pp. 313–326, 2010.
[27]
N. Mizushima and B. Levine, “Autophagy in mammalian development and differentiation,” Nature Cell Biology, vol. 12, no. 9, pp. 823–830, 2010.
[28]
D. J. Klionsky, H. Abeliovich, P. Agostinis, et al., “Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes,” Autophagy, vol. 4, no. 2, pp. 151–175, 2008.
[29]
M. Komatsu, S. Waguri, M. Koike et al., “Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice,” Cell, vol. 131, no. 6, pp. 1149–1163, 2007.
[30]
G. Bj？rk？y, T. Lamark, A. Brech et al., “p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death,” Journal of Cell Biology, vol. 171, no. 4, pp. 603–614, 2005.
[31]
G. R. Steinberg and B. E. Kemp, “AMPK in health and disease,” Physiological Reviews, vol. 89, no. 3, pp. 1025–1078, 2009.
[32]
R. Zoncu, A. Efeyan, and D. M. Sabatini, “MTOR: From growth signal integration to cancer, diabetes and ageing,” Nature Reviews Molecular Cell Biology, vol. 12, no. 1, pp. 21–35, 2011.
[33]
S. Wullschleger, R. Loewith, and M. N. Hall, “TOR signaling in growth and metabolism,” Cell, vol. 124, no. 3, pp. 471–484, 2006.
[34]
S. Sengupta, T. R. Peterson, and D. M. Sabatini, “Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress,” Molecular Cell, vol. 40, no. 2, pp. 310–322, 2010.
[35]
C. L. Yun and J. R. Zierath, “AMP-activated protein kinase signaling in metabolic regulation,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 1776–1783, 2006.
[36]
P. J. A. M. Plomp, P. B. Gordon, A. J. Meijer, H. Hoyvik, and P. O. Seglen, “Energy dependence of different steps in the autophagic lysosomal pathway,” The Journal of Biological Chemistry, vol. 264, no. 12, pp. 6699–6704, 1989.
[37]
M. Zhao and D. J. Klionsky, “AMPK-dependent phosphorylation of ULK1 induces autophagy,” Cell Metabolism, vol. 13, no. 2, pp. 119–120, 2011.
[38]
K. Inoki, Y. Li, T. Xu, and K.-L. Guan, “Rheb GTpase is a direct target of TSC2 GAP activity and regulates mTOR signaling,” Genes and Development, vol. 17, no. 15, pp. 1829–1834, 2003.
[39]
M. Laplante and D. M. Sabatini, “MTOR signaling in growth control and disease,” Cell, vol. 149, no. 2, pp. 274–293, 2012.
[40]
K. Inoki, Y. Li, T. Zhu, J. Wu, and K.-L. Guan, “TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling,” Nature Cell Biology, vol. 4, no. 9, pp. 648–657, 2002.
[41]
Y. Sancak, T. R. Peterson, Y. D. Shaul et al., “The rag GTPases bind raptor and mediate amino acid signaling to mTORC1,” Science, vol. 320, no. 5882, pp. 1496–1501, 2008.
[42]
Y. Sancak, L. Bar-Peled, R. Zoncu, A. L. Markhard, S. Nada, and D. M. Sabatini, “Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids,” Cell, vol. 141, no. 2, pp. 290–303, 2010.
[43]
L. Liu, D. R. Wise, J. A. Diehl, and M. C. Simon, “Hypoxic reactive oxygen species regulate the integrated stress response and cell survival,” The Journal of Biological Chemistry, vol. 283, no. 45, pp. 31153–31162, 2008.
[44]
S. Sakon, X. Xue, M. Takekawa et al., “NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death,” The EMBO Journal, vol. 22, no. 15, pp. 3898–3909, 2003.
[45]
J. L. Webber and S. A. Tooze, “Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP,” The EMBO journal, vol. 29, no. 1, pp. 27–40, 2010.
[46]
C. Vives-Bauza, C. Zhou, Y. Huang et al., “PINK1-dependent recruitment of Parkin to mitochondria in mitophagy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 1, pp. 378–383, 2010.
[47]
S. Geisler, K. M. Holmstr？m, D. Skujat et al., “PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1,” Nature Cell Biology, vol. 12, no. 2, pp. 119–131, 2010.
[48]
A. J. Majmundar, W. J. Wong, and M. C. Simon, “Hypoxia-inducible factors and the response to hypoxic stress,” Molecular Cell, vol. 40, no. 2, pp. 294–309, 2010.
[49]
N. M. Mazure and J. Pouysségur, “Hypoxia-induced autophagy: cell death or cell survival?” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 177–180, 2010.
[50]
G. Bellot, R. Garcia-Medina, P. Gounon et al., “Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains,” Molecular and Cellular Biology, vol. 29, no. 10, pp. 2570–2581, 2009.
[51]
S. A. Tooze and T. Yoshimori, “The origin of the autophagosomal membrane,” Nature Cell Biology, vol. 12, no. 9, pp. 831–835, 2010.
[52]
A. Buchberger, B. Bukau, and T. Sommer, “Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms,” Molecular Cell, vol. 40, no. 2, pp. 238–252, 2010.
[53]
M. Ogata, S.-I. Hino, A. Saito et al., “Autophagy is activated for cell survival after endoplasmic reticulum stress,” Molecular and Cellular Biology, vol. 26, no. 24, pp. 9220–9231, 2006.
[54]
K. M. A. Rouschop, T. Van Den Beucken, L. Dubois et al., “The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5,” Journal of Clinical Investigation, vol. 120, no. 1, pp. 127–141, 2010.
[55]
F. N. Ziyadeh and G. Wolf, “Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy,” Current Diabetes Reviews, vol. 4, no. 1, pp. 39–45, 2008.
[56]
J. A. Jefferson, S. J. Shankland, and R. H. Pichler, “Proteinuria in diabetic kidney disease: a mechanistic viewpoint,” Kidney International, vol. 74, no. 1, pp. 22–36, 2008.
[57]
M. E. Pagtalunan, P. L. Miller, S. Jumping-Eagle et al., “Podocyte loss and progressive glomerular injury in type II diabetes,” Journal of Clinical Investigation, vol. 99, no. 2, pp. 342–348, 1997.
[58]
K. Asanuma, I. Tanida, I. Shirato et al., “MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis,” The FASEB Journal, vol. 17, no. 9, pp. 1165–1167, 2003.
[59]
N. Mizushima, A. Yamamoto, M. Matsui, T. Yoshimori, and Y. Ohsumi, “In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker,” Molecular Biology of the Cell, vol. 15, no. 3, pp. 1101–1111, 2004.
[60]
S. Sato, H. Kitamura, A. Adachi, Y. Sasaki, and M. Ghazizadeh, “Two types of autophagy in the podocytes in renal biopsy specimens: ultrastructural study,” Journal of Submicroscopic Cytology and Pathology, vol. 38, no. 2-3, pp. 167–174, 2006.
[61]
L. Fang, Y. Zhou, H. Cao, et al., “Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury,” PLoS One, vol. 8, no. 4, Article ID e60546, 2013.
[62]
D. P. Cinà, T. Onay, A. Paltoo et al., “Inhibition of MTOR disrupts autophagic flux in podocytes,” Journal of the American Society of Nephrology, vol. 23, no. 3, pp. 412–420, 2012.
[63]
M. G？del, B. Hartleben, N. Herbach et al., “Role of mTOR in podocyte function and diabetic nephropathy in humans and mice,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2197–2209, 2011.
[64]
T. W. Meyer, P. H. Bennett, and R. G. Nelson, “Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria,” Diabetologia, vol. 42, no. 11, pp. 1341–1344, 1999.
[65]
T. Weide and T. B. Huber, “Implications of autophagy for glomerular aging and disease,” Cell and Tissue Research, vol. 343, no. 3, pp. 467–473, 2011.
[66]
K. Inoki and T. B. Huber, “Mammalian target of rapamycin signaling in the podocyte,” Current Opinion in Nephrology and Hypertension, vol. 21, no. 3, pp. 251–257, 2012.
[67]
Y. Yang, J. Wang, L. Qin et al., “Rapamycin prevents early steps of the development of diabetic nephropathy in rats,” American Journal of Nephrology, vol. 27, no. 5, pp. 495–502, 2007.
[68]
K. Sharma, S. RamachandraRao, G. Qiu et al., “Adiponectin regulates albuminuria and podocyte function in mice,” Journal of Clinical Investigation, vol. 118, no. 5, pp. 1645–1656, 2008.
[69]
R. A. Risdon, J. C. Sloper, and H. E. De Wardener, “Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis,” The Lancet, vol. 2, no. 7564, pp. 363–366, 1968.
[70]
S. Liu, B. Hartleben, O. Kretz, et al., “Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury,” Autophagy, vol. 8, no. 5, pp. 826–837, 2012.
[71]
K. Yamahara, S. Kume, D. Koya, et al., “Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions,” Journal of the American Society of Nephrology, vol. 24, no. 11, pp. 1769–1781, 2013.
[72]
M. Kitada, A. Takeda, T. Nagai, H. Ito, K. Kanasaki, and D. Koya, “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,” Experimental Diabetes Research, vol. 2011, Article ID 908185, 11 pages, 2011.
[73]
A. D. Balgi, B. D. Fonseca, E. Donohue et al., “Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling,” PLoS ONE, vol. 4, no. 9, Article ID e7124, 2009.
[74]
Z.-X. Xu, J. Liang, V. Haridas et al., “A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase,” Cell Death and Differentiation, vol. 14, no. 11, pp. 1948–1957, 2007.
[75]
E. F. C. Blommaart, J. J. F. P. Luiken, P. J. E. Blommaart, G. M. Van Woerkom, and A. J. Meijer, “Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes,” The Journal of Biological Chemistry, vol. 270, no. 5, pp. 2320–2326, 1995.
[76]
W. Lieberthal and J. S. Levine, “The role of the mammalian target of rapamycin (mTOR) in renal disease,” Journal of the American Society of Nephrology, vol. 20, no. 12, pp. 2493–2502, 2009.
[77]
F. C. Fervenza, P. M. Fitzpatrick, J. Mertz et al., “Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies,” Nephrology Dialysis Transplantation, vol. 19, no. 5, pp. 1288–1292, 2004.
[78]
T. B. Huber, G. Walz, and E. W. Kuehn, “MTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression,” Kidney International, vol. 79, no. 5, pp. 502–511, 2011.
[79]
J. Kim, M. Kundu, B. Viollet, and K.-L. Guan, “AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1,” Nature Cell Biology, vol. 13, no. 2, pp. 132–141, 2011.
[80]
R. Rachmani, I. Slavachevski, Z. Levi, B.-S. Zadok, Y. Kedar, and M. Ravid, “Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications,” European Journal of Internal Medicine, vol. 13, no. 7, pp. 428–433, 2002.
[81]
J.-D. Lalau, “Lactic acidosis induced by metformin: incidence, management and prevention,” Drug Safety, vol. 33, no. 9, pp. 727–740, 2010.
[82]
M.-J. Lee, D. Feliers, M. M. Mariappan et al., “A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy,” American Journal of Physiology—Renal Physiology, vol. 292, no. 2, pp. F617–F627, 2007.
[83]
S. Sarkar, J. E. Davies, Z. Huang, A. Tunnacliffe, and D. C. Rubinsztein, “Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein,” The Journal of Biological Chemistry, vol. 282, no. 8, pp. 5641–5652, 2007.
[84]
S. Sarkar, R. A. Floto, Z. Berger et al., “Lithium induces autophagy by inhibiting inositol monophosphatase,” Journal of Cell Biology, vol. 170, no. 7, pp. 1101–1111, 2005.
[85]
A. Williams, S. Sarkar, P. Cuddon et al., “Novel targets for Huntington's disease in an mTOR-independent autophagy pathway,” Nature Chemical Biology, vol. 4, no. 5, pp. 295–305, 2008.
[86]
C.-T. Chien, S.-K. Shyue, and M.-K. Lai, “Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy,” Transplantation, vol. 84, no. 9, pp. 1183–1190, 2007.
[87]
C. Suzuki, Y. Isaka, Y. Takabatake et al., “Participation of autophagy in renal ischemia/reperfusion injury,” Biochemical and Biophysical Research Communications, vol. 368, no. 1, pp. 100–106, 2008.
[88]
K. Inoue, H. Kuwana, Y. Shimamura et al., “Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo,” Clinical and Experimental Nephrology, vol. 14, no. 2, pp. 112–122, 2010.
[89]
C. Ebato, T. Uchida, M. Arakawa et al., “Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet,” Cell Metabolism, vol. 8, no. 4, pp. 325–332, 2008.
[90]
H. S. Jung, K. W. Chung, J. Won Kim et al., “Loss of autophagy diminishes pancreatic β cell mass and function with resultant hyperglycemia,” Cell Metabolism, vol. 8, no. 4, pp. 318–324, 2008.
[91]
Z.-F. Chen, Y.-B. Li, J.-Y. Han et al., “The double-edged effect of autophagy in pancreatic beta cells and diabetes,” Autophagy, vol. 7, no. 1, pp. 12–16, 2011.
[92]
R. Singh, Y. Xiang, Y. Wang et al., “Autophagy regulates adipose mass and differentiation in mice,” Journal of Clinical Investigation, vol. 119, no. 11, pp. 3329–3339, 2009.
[93]
Y. Zhang, S. Goldman, R. Baerga, Y. Zhao, M. Komatsu, and S. Jin, “Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 47, pp. 19860–19865, 2009.
[94]
C. Zhang and A. M. Cuervo, “Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function,” Nature Medicine, vol. 14, no. 9, pp. 959–965, 2008.
[95]
T. Shintani and D. J. Klionsky, “Autophagy in health and disease: a double-edged sword,” Science, vol. 306, no. 5698, pp. 990–995, 2004.
[96]
Y. Kondo, T. Kanzawa, R. Sawaya, and S. Kondo, “The role of autophagy in cancer development and response to therapy,” Nature Reviews Cancer, vol. 5, no. 9, pp. 726–734, 2005.
