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

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.

• Authors: Marisa D Covington, Rick G Schnellmann
• Journal: Kidney international (Kidney Int) Vol. 81 Issue 4 Pg. 391-400 (Feb 2012) ISSN: 1523-1755 [Electronic] United States
• PMID: 22012129 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• RNA, Messenger
• RNA, Small Interfering
• Streptozocin
• Calpain
• Caspase 3
• calpain 10
• ATP synthase beta subunit, rat
• Mitochondrial Proton-Translocating ATPases
• Glucose

Topics

• Animals
• Apoptosis
• Calpain (drug effects, metabolism)
• Caspase 3 (metabolism)
• Cells, Cultured
• Diabetes Mellitus (chemically induced)
• Diabetic Nephropathies (enzymology, metabolism)
• Down-Regulation
• Female
• Glucose (metabolism, pharmacology)
• Kidney Tubules, Proximal (enzymology, physiopathology)
• Male
• Mice
• Mice, Obese
• Mitochondria (enzymology, physiology)
• Mitochondrial Proton-Translocating ATPases (metabolism)
• RNA, Messenger (metabolism)
• RNA, Small Interfering (pharmacology)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Streptozocin