REDD1-dependent GSK3β signaling in podocytes promotes canonical NF-κB activation in diabetic nephropathy.

Abstract

Increasing evidence supports the role of an augmented immune response in the early development and progression of renal complications caused by diabetes. We recently demonstrated that podocyte-specific expression of stress response protein regulated in development and DNA damage response 1 (REDD1) contributes to activation of the pro-inflammatory transcription factor NF-κB in the kidney of diabetic mice. The studies here were designed to define the specific signaling events whereby REDD1 promotes NF-κB activation in the context of diabetic nephropathy. Streptozotocin (STZ)-induced diabetes promoted activation of glycogen synthase kinase 3β (GSK3β) in the kidney, which was prevented by REDD1 ablation. REDD1 was necessary and sufficient to enhance GSK3β activity in human podocyte cultures exposed to hyperglycemic conditions. GSK3β suppression prevented NF-κB activation and normalized the expression of pro-inflammatory factors in podocytes exposed to hyperglycemic conditions. In the kidneys of diabetic mice and in podocytes exposed to hyperglycemic conditions, REDD1-dependent GSK3β signaling promoted activation of the inhibitor of κB (IκB) kinase (IKK) complex upstream of NF-κB. GSK3β knockdown in podocytes exposed to hyperglycemic conditions reduced macrophage chemotaxis. Similarly, in diabetic mice treated with a GSK3 inhibitor, immune cell infiltration in the kidneys was reduced. Overall, the data support a model wherein hyperglycemia amplifies the activation of GSK3β in a REDD1-dependent manner, leading to canonical NF-κB signaling and an augmented renal immune response in diabetic nephropathy.