| Authors |
Mima A, Ohshiro Y, Kitada M, Matsumoto M, Geraldes P, Li C, Li Q, White GS,
Cahill C, Rask-Madsen C, King GL
|
| Submitted By |
Christian Rask-Madsen on 12/10/2012 |
| Status |
Published |
| Journal |
Kidney international |
| Year |
2011 |
| Date Published |
4/1/2011 |
| Volume : Pages |
79 : 883 - 896 |
| PubMed Reference |
21228767 |
| Abstract |
Insulin resistance has been associated with the progression of chronic kidney
disease in both diabetes and obesity. In order to determine the cellular
mechanisms contributing to this, we characterized insulin signaling in renal
tubules and glomeruli during diabetic and insulin-resistant states using
streptozotocin-diabetic and Zucker fatty-insulin-resistant rats. Compared with
nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin
receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and
glycogen synthase kinase 3a were selectively inhibited in the glomeruli but not
in the renal tubules of both respective models. Protein, but not mRNA levels of
IRS1, was decreased only in the glomeruli of streptozotocin-diabetic rats likely
due to increased ubiquitination. Treatment with the protein kinase C-ß
inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression.
In glomerular endothelial cells, high glucose inhibited the phosphorylation of
Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3a;
decreased IRS1 protein expression and increased its association with ubiquitin.
Overexpression of IRS1 or the addition of ruboxistaurin reversed the inhibitory
effects of high glucose. Thus, loss of insulin's effect on endothelial nitric
oxide synthase and glycogen synthase kinase 3a activation may contribute to the
glomerulopathy observed in diabetes and obesity.
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