REDD1 deletion prevents the development of renal dysfunction in diabetic mice.

Diabetic kidney disease (DKD) results in chronic loss of kidney function and is the leading cause of end-stage renal disease. Hyperglycemia is an important mediator of diabetic complications, including DKD. Hyperglycemic conditions promote renal redox imbalance, resulting in glomerular/tubular damage and compromised renal function. Presently, much remains unknown regarding the molecular events that contribute to development of oxidative stress in the context of DKD. In the present study, we evaluated the hypothesis that hyperglycemic conditions promote expression of the stress response protein REDD1 in the kidney in a manner that contributes to the development of renal pathology and compromised function. After 16 weeks of streptozotocin (STZ)-induced diabetes, urinary albumin to creatinine ratio and kidney to body weight ratios were elevated in wild-type mice. These markers of renal dysfunction were associated with increased renal REDD1 expression. In contrast to wild-type mice, REDD1 knockout (KO) mice failed to exhibit a diabetes-induced deficit in kidney function. Histopathologic examination of the kidney found glomerular damage in diabetic wild-type mice, but not in diabetic REDD1 KO mice. In cultured human podocytes, exposure to hyperglycemic conditions elevated REDD1 expression concomitant with increased oxidative stress and cell death. Oxidative stress and cellular apoptosis were not observed in podocyte cultures upon REDD1 deletion. Similarly, REDD1 deletion prevented diabetes-induced oxidative stress in the kidney in coordination with upregulation of the Nrf2 antioxidant response. These findings provide new insights into how diabetes and hyperglycemia contribute to development of renal pathology and support the possibility that therapeutics targeting REDD1 could be beneficial in the context of DKD.