期刊
KIDNEY INTERNATIONAL
卷 81, 期 4, 页码 391-400出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ki.2011.356
关键词
acute kidney injury; apoptosis; diabetic nephropathy; hyperglycemia; mitochondria
资金
- NIEHS [ES-012239]
- NIGMS [GM-084147]
- Biomedical Laboratory of the Department of Veterans Affairs
- National Institutes of Health [T32 HL007260, C06 RR-015455]
Whereas most calpains are cytosolic proteases, calpain 10 is resident in mitochondria and is important in mitochondria! homeostasis. Because calpain 10 has been implicated in type 2 diabetes, we studied its possible role in diabetes-induced renal dysfunction. We treated renal proximal tubular cells with high glucose (17 mmol/l) and found decreased mitochondrial calpain 10 mRNA and protein at 96h compared with cells incubated with 0 or 5 mmol/l glucose or 17 mmol/l D-mannitol. High glucose increased mitochondrial calpain 10 substrates (NDUFB8 and ATP synthase p), decreased basal and uncoupled respiration, and initiated cell apoptosis as indicated by cleaved caspase 3 and nuclear condensation. Renal calpain 10 protein and mRNA were specifically decreased in streptozotocin-induced diabetic rats with kidney dysfunction, and in diabetic ob/ob mice. In agreement with our in vitro data, the kidneys of streptozotocin-induced diabetic rats had elevated calpain 10 substrates and cleaved caspase 3. Finally, specific siRNA-induced knockdown of calpain 10 in the proximal tubules of control rats resulted in decreased renal function as evidenced by increased serum creatinine, and increased caspase 3 cleavage compared with rats receiving scrambled siRNA. Thus, the glucose-induced loss of calpain 10 in vivo results in renal cell apoptosis and organ failure through accumulation of mitochondrial calpain 10 substrates and mitochondrial dysfunction. Whether this is a major cause of the decreased renal function in diabetic nephropathy will require further studies. Kidney International (2012) 81, 391-400; doi:10.1038/ki.2011.356; published online 19 October 2011
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