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Abstract: FR-PO366

Stress Response Protein REDD1 Sustains the Chronic Inflammatory Response in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic


  • Sunilkumar, Siddharth, Penn State College of Medicine, Hershey, Pennsylvania, United States
  • Dennis, Michael D., Penn State College of Medicine, Hershey, Pennsylvania, United States

Diabetic nephropathy (DN) is one of the most common and severe complications of diabetes. We recently demonstrated a role for the stress response protein REDD1 in development of renal complications in DN. However, there remains a significant gap in our understanding of the molecular events whereby REDD1 contributes to the development of renal dysfunction. Herein, we investigated the hypothesis that diabetes-induced REDD1 expression acts to exacerbate pro-inflammatory NF-κB signaling and consequently development of renal inflammation.


REDD1+/+ and REDD1-/- mice were administered low dose streptozotocin to induce diabetes. Kidneys were isolated after 16 weeks of diabetes, weighed, and analyzed for protein and mRNA expression. Spot urine albumin and creatinine levels were assayed. Kidneys were fixed and renal sections were visualized by immunofluorescence microscopy. Complementary analyses were performed with conditionally immortalized human podocyte cultures exposed to hyperglycemic conditions. Inhibition of SLGT2 or GSK3 was achieved by dapagliflozin or VP3.15 administration, respectively. Nuclear NF-κB activity was estimated by luciferase assay.


Diabetes increased REDD1 expression in the kidney and promoted albuminuria and renal immune cell infiltration. In diabetic mice treated with dapagliflozin, blood glucose concentrations were reduced and both REDD1 expression and immune cell infiltration were attenuated. In contrast with REDD1+/+ mice, REDD1-/- mice did not exhibit an increase in pro-inflammatory marker expression or renal macrophage infiltration with diabetes. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1 expression, which was required for activation of both NF-κB and the NLRP3 inflammasome. Upregulated expression of NF-κB target genes and IL1β production by podocytes exposed to hyperglycemic conditions was prevented by REDD1 deletion. REDD1 acted via an Akt-GSK3β signaling axis, as GSK3β inhibition prevented diabetes-induced NF-κB activation and reduced immune cell infiltration in kidneys of diabetic mice.


These findings demonstrate a role for REDD1-dependent GSK3 signaling in diabetes-induced renal pathology and support the possibility that therapeutics targeting REDD1 or GSK3 could be beneficial in the context of DN.


  • Other NIH Support