Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy

被引:686
作者
Susztak, K
Raff, AC
Schiffer, M
Böttinger, EP
机构
[1] Mt Sinai Sch Med, Div Nephrol, Dept Med, New York, NY 10029 USA
[2] Albert Einstein Coll Med, Dept Med, Div Nephrol, Bronx, NY 10467 USA
关键词
D O I
10.2337/diabetes.55.01.06.db05-0894
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyperglycemia in Ins2(Akita) (Akita) mice with type 1 diabetes and Lepr(db/db) (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37% reduction) and db/db (27% reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular reactive oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapoptotic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apoptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic nephropathy in murine type 1 and type 2 diabetic models.
引用
收藏
页码:225 / 233
页数:9
相关论文
共 50 条
[41]   Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy [J].
Susztak, K ;
Ciccone, E ;
McCue, P ;
Sharma, K ;
Böttinger, EP .
PLOS MEDICINE, 2005, 2 (02) :152-161
[42]   Molecular profiling of diabetic mouse kidney reveals novel genes linked to glomerular disease [J].
Susztak, K ;
Böttinger, E ;
Novetsky, A ;
Liang, D ;
Zhu, YQ ;
Ciccone, E ;
Wu, DN ;
Dunn, S ;
McCue, P ;
Sharma, K .
DIABETES, 2004, 53 (03) :784-794
[43]   Genomic strategies for diabetic nephropathy [J].
Susztak, K ;
Sharma, K ;
Schiffer, M ;
McCue, P ;
Ciccone, E ;
Böttinger, EP .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 :S271-S278
[44]   Short-term and hyperglycemia produces oxidative damage and apoptosis in neurons [J].
Vincent, AM ;
McLean, LL ;
Backus, C ;
Feldman, EL .
FASEB JOURNAL, 2005, 19 (01) :638-+
[45]   Urinary excretion of viable podocytes in health and renal disease [J].
Vogelmann, SU ;
Nelson, WJ ;
Myers, BD ;
Lemley, KV .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2003, 285 (01) :F40-F48
[46]   Glucose, glycation, and RAGE: Implications for amplification of cellular dysfunction in diabetic nephropathy [J].
Wendt, T ;
Tanji, N ;
Guo, HC ;
Hudson, BI ;
Bierhaus, A ;
Ramasamy, R ;
Arnold, B ;
Nawroth, PP ;
Yan, SF ;
D'Agati, V ;
Schmidt, M .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (05) :1383-1395
[47]   From the periphery of the glomerular capillary wall toward the center of disease - Podocyte injury comes of age in diabetic nephropathy [J].
Wolf, G ;
Chen, SD ;
Ziyadeh, FN .
DIABETES, 2005, 54 (06) :1626-1634
[48]   Mediators of diabetic renal disease:: The case for TGF-β as the major mediator [J].
Ziyadeh, FN .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2004, 15 (01) :S55-S57
[49]   Overview: Combating diabetic nephropathy [J].
Ziyadeh, FN ;
Sharma, K .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (05) :1355-1357
[50]   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 [J].
Ziyadeh, FN ;
Hoffman, BB ;
Han, DC ;
Iglesias-de la Cruz, MC ;
Hong, SW ;
Isono, M ;
Chen, S ;
McGowan, TA ;
Sharma, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (14) :8015-8020