Chronic high glucose downregulates mitochondrial calpain 10 and contributes to renal cell death and diabetes-induced renal injury

Marisa D. Covington, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Whereas most calpains are cytosolic proteases, calpain 10 is resident in mitochondria and is important in mitochondrial 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 96 h 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 Β), 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.

Original languageEnglish (US)
Pages (from-to)391-400
Number of pages10
JournalKidney International
Volume81
Issue number4
DOIs
StatePublished - Feb 2 2012
Externally publishedYes

Keywords

  • acute kidney injury
  • apoptosis
  • diabetic nephropathy
  • hyperglycemia
  • mitochondria

ASJC Scopus subject areas

  • Nephrology

Fingerprint

Dive into the research topics of 'Chronic high glucose downregulates mitochondrial calpain 10 and contributes to renal cell death and diabetes-induced renal injury'. Together they form a unique fingerprint.

Cite this