Dataset Information

Inactivation of p66Shc Decreases Afferent Arteriolar KATP Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats.

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.

SUBMITTER: Miller BS

PROVIDER: S-EPMC6198347 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inactivation of p66Shc Decreases Afferent Arteriolar K<sub>ATP</sub> Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats.

Miller Bradley S BS Blumenthal Shoshana R SR Shalygin Alexey A Wright Kevin D KD Staruschenko Alexander A Imig John D JD Sorokin Andrey A

Diabetes 20180821 11

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 K<sub>ATP</sub> 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 express ...[more]

PMID: 30131395

Similar Datasets

Project description:Aims:Type 2 diabetes (T2D) is strongly associated with cardiovascular morbidity and mortality in patients. Vascular large conductance Ca2+-activated potassium (BK) channels, composed of four pore-forming ? subunits (BK-?), and four regulatory ?1 subunits (BK-?1), are densely expressed in coronary arterial smooth muscle cells (SMCs) and play an important role in regulating vascular tone and myocardial perfusion. However, the role of BK channels in coronary microvascular dysfunction of human subjects with diabetes is unclear. In this study, we examined BK channel function and protein expression, and BK channel-mediated vasodilation in freshly isolated coronary arterioles from T2D patients. Methods and results:Atrial tissues were obtained from 16 patients with T2D and 25 matched non-diabetic subjects during cardiopulmonary bypass procedure. Microvessel videomicroscopy and immunoblot analysis were performed in freshly dissected coronary arterioles and inside-out single BK channel currents was recorded in enzymatically isolated coronary arteriolar SMCs. We found that BK channel sensitivity to physiological Ca2+ concentration and voltage was downregulated in the coronary arteriolar SMCs of diabetic patients, compared with non-diabetic controls. BK channel kinetics analysis revealed that there was significant shortening of the mean open time and prolongation of the mean closed time in diabetic patients, resulting in a remarkable reduction of the channel open probability. Functional studies showed that BK channel activation by dehydrosoyasaponin-1 was diminished and that BK channel-mediated vasodilation in response to shear stress was impaired in diabetic coronary arterioles. Immunoblot experiments confirmed that the protein expressions of BK-? and BK-?1 subunits were significantly downregulated, but the ratio of BK-?/BK-?1 was unchanged in the coronary arterioles of T2D patients. Conclusions:Our results demonstrated for the first time that BK channel function and BK channel-mediated vasodilation were abnormal in the coronary microvasculature of diabetic patients, due to decreased protein expression and altered intrinsic properties of BK channels.

Dataset Information

Inactivation of p66Shc Decreases Afferent Arteriolar KATP Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats.

Publications

Inactivation of p66Shc Decreases Afferent Arteriolar K<sub>ATP</sub> Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets