Podocyte-Specific Expression of the Stress Response Protein REDD1 is Necessary for Diabetes-induced Podocytopenia

ABSTRACT

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and effective treatment modalities that fully address its molecular etiology are lacking. Prior studies support that the stress response protein REDD1 (Regulated in Development and DNA Damage 1) contributes to the development of diabetic complications. This study investigated a potential role for REDD1 expression in podocytes in diabetes-induced podocyte loss and compromised glomerular filtration. Podocyte-specific REDD1 deletion protected against renal injury, as evidenced by reduced albuminuria, glomerular hypertrophy, and mesangial matrix deposition in streptozotocin (STZ)-induced diabetic mice. Podocyte-specific REDD1 expression was required for diabetes-induced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basement membrane and foot process architecture in diabetic mice. In the kidneys of diabetic mice and in human podocyte cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the transient receptor potential canonical 6 (TRPC6) channel. More specifically, REDD1 promoted NF-κB-dependent transcription of TRPC6, intracellular calcium entry, and cytoskeletal remodeling under hyperglycemic conditions. Overall, the findings provide new insight into the role of podocyte-specific REDD1 expression in renal pathology and support the possibility that therapeutics targeting REDD1 in podocytes could be beneficial for DN.

MANUSCRIPT HIGHLIGHTS

· Diabetes-induced albuminuria and reduced glomerular slit diaphragm (SD) proteins were associated with increased kidney REDD1 protein abundance.

· Podocyte-specific deletion of REDD1 attenuated diabetes-induced SD protein reduction and podocyte loss.

· REDD1 was required for NF-κB-dependent TRPC6 expression and increased cytoplasmic calcium levels in podocytes.

· Podocyte-specific expression of REDD1 was necessary for altered glomerular architecture and albuminuria in diabetic mice.