Podocyte-Specific Expression of the Stress Response Protein REDD1 Is Necessary for Diabetes-Induced Podocytopenia

Diabetic nephropathy (DN) is the leading cause of endstage renal disease, and effective treatmentmodalities that fully address itsmolecular etiology are lacking. Prior studies support that the stress response protein REDD1 (regulated in development and DNA damage 1) contributes to the development of diabetes 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. Podocytespecific REDD1 expression was required for diabetesinduced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basementmembrane and foot process architecture in diabetic mice. In the kidneys of diabeticmice 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 nuclear factorkB– 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 forDN.