Abstract: TH-OR133

Deletion of Adaptor Protein p66Shc Decreases Afferent Arteriolar KATP Channel Activity and Decreases Renal Damage in Diabetic Dahl SS Rats

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Sorokin, Andrey, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Miller, Bradley S., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Blumenthal, Shoshana R., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Imig, John D., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

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.

Methods

This study tested the hypothesis that p66Shc KO Dahl SS rats with STZ-induced diabetes are protected from glomerular injury because afferent arterioles do not exhibit enhanced KATP channel activity. Afferent arteriolar responses to the KATP channel opener pinacidil and the KATP channel blocker glibenclamide were assessed in Dahl SS, Dahl SS p66Shc KO, Dahl SS with STZ-induced diabetes, and Dahl SS p66Shc KO with STZ-induced diabetes rats. Afferent arteriolar diameter responses were determined using the juxtamedullary nephron technique six weeks following induction of STZ diabetes. Hyperglycemia, excessive urination, body weight, albuminuria and glomerular injury was evaluated in all rat groups to monitor the progression of diabetic nephropathy.

Results

Afferent arteriolar diameters at 100 mmHg averaged 22.9 ± 0.9 μm (n=8) in Dahl SS rats, 21.1 ± 0.8 μm (n=6) Dahl SS p66Shc KO. Dahl SS with STZ-induced diabetes rats had a significant increase in the afferent arteriolar diameter (24.7 ± 1.3 μm; n=6). Inversely, Dahl SS p66Shc KO with STZ-induced diabetes rats did not have increased afferent arteriolar diameters (22.1 ± 1.2 μm; n=6). Afferent arteriolar dilator responses to pinacidil were not different between Dahl SS rats and Dahl SS p66Shc KO. However; Dahl SS with STZ-induced diabetes but not Dahl SS p66Shc KO with STZ-induced diabetes rats had an increased vasodilator response to pinacidil. Likewise, the KATP inhibitor gibenclamide (30 µM) resulted in a greater decrease in afferent arteriolar diameter in Dahl SS & STZ-induced diabetes (23 ± 4%, n =6) compared to Dahl SS p66Shc KO & STZ-induced diabetes (13 ± 2%, n =6). The glomerular injury was mitigated in Dahl SS p66Shc KO with STZ-induced diabetes.

Conclusion

Taken together, these results indicate that increased afferent arteriolar KATP channel activity contributes to increased diameters and renal injury in Dahl SS & STZ-induced diabetes. Moreover, deletion of the adaptor protein p66Shc decreases afferent arteriolar KATP channel activity and decreases renal damage in diabetic Dahl SS rats.

Funding

  • NIDDK Support