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REDD1 ablation attenuates the development of renal complications in diabetic mice

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posted on 2022-08-19, 14:34 authored by Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, William P. Miller, Han Chen, Kebin Hu, Scot R. Kimball, Michael D. Dennis

Chronic hyperglycemia contributes to development of diabetic kidney disease by promoting glomerular injury. In this study, we evaluated the hypothesis that hyperglycemic conditions promote expression of the stress response protein regulated in development and DNA damage response 1 (REDD1) in the kidney in a manner that contributes to the development of oxidative stress and renal injury. After 16 weeks of streptozotocin (STZ)-induced diabetes, albuminuria and renal hypertrophy were observed in wildtype mice coincident with increased renal REDD1 expression. In contrast, diabetic REDD1 knockout (KO) mice did not exhibit impaired renal physiology. Histopathologic examination revealed that glomerular damage including mesangial expansion, matrix deposition, and podocytopenia in the kidneys of diabetic wildtype mice were reduced or absent in diabetic REDD1 KO mice. In cultured human podocytes, exposure to hyperglycemic conditions enhanced REDD1 expression, increased reactive oxygen species (ROS) levels, and promoted cell death. In both the kidney of diabetic mice and in podocyte cultures exposed to hyperglycemic conditions, REDD1 deletion reduced ROS and prevented podocyte loss. Benefits of REDD1 deletion were recapitulated by pharmacological GSK3β suppression, supporting a role for REDD1-dependent GSK3β activation in diabetes-induced oxidative stress and renal defects. The results support a role for REDD1 in diabetes-induced renal complications.

Funding

This research was supported by the American Diabetes Association Pathway to Stop Diabetes grant 1-14-INI-04, National Institutes of Health grants R01 EY029702 and R01 EY032879 (to MDD), and a Children’s Miracle Network Trainee Research Grant (to SS).

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