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Inactivation of p66Shc Decreases Afferent Arteriolar KATP Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats. Diabetes 2018 Nov;67(11):2206-2212

Date

08/23/2018

Pubmed ID

30131395

Pubmed Central ID

PMC6198347

DOI

10.2337/db18-0308

Scopus ID

2-s2.0-85055169170 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

Increased expression of adaptor protein p66Shc has been associated with progression of diabetic nephropathy. Afferent arteriolar dilation and glomerular hyperfiltration in diabetes are due to increased KATP channel availability and activity. Hyperglycemia was induced in Dahl salt-sensitive (SS) rats in a model of diabetes induced by streptozotocin (STZ). Renal injury was evaluated in SS rats and genetically modified SS rats either lacking p66Shc (p66Shc knockout [p66ShcKO]) or expressing p66Shc mutant (p66Shc-S36A). Afferent arteriolar diameter responses during STZ-induced hyperfiltration were determined by using the juxtamedullary nephron technique. Albuminuria and glomerular injury were mitigated in p66ShcKO and p66Shc-S36A rats with STZ-induced diabetes. SS rats with STZ-induced diabetes had significantly increased afferent arteriolar diameter, whereas p66ShcKO and p66Shc-S36A rats did not. SS rats with STZ-induced diabetes, but not p66ShcKO or p66Shc-S36A rats with STZ-induced diabetes, had an increased vasodilator response to the KATP channel activator pinacidil. Likewise, the KATP inhibitor glibenclamide resulted in a greater decrease in afferent arteriolar diameter in SS rats with STZ-induced diabetes than in STZ-treated SS p66ShcKO and p66Shc-S36A rats. Using patch-clamp electrophysiology, we demonstrated that p66ShcKO decreases KATP channel activity. These results indicate that inactivation of the adaptor protein p66Shc decreases afferent arteriolar KATP channel activity and decreases renal damage in diabetic SS rats.

Author List

Miller BS, Blumenthal SR, Shalygin A, Wright KD, Staruschenko A, Imig JD, Sorokin A

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Arterioles
Diabetes Mellitus, Experimental
Diabetic Nephropathies
KATP Channels
Kidney
Pinacidil
Rats
Rats, Inbred Dahl
Rats, Transgenic
Src Homology 2 Domain-Containing, Transforming Protein 1
Vasodilation
Vasodilator Agents