Abstract: SA-PO229
Diabetes-Induced Renal Inflammation Is Facilitated by Expression of the Stress Response Protein REDD1
Session Information
- Diabetic Kidney Disease: Basic - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Sunilkumar, Siddharth, Penn State College of Medicine, Hershey, Pennsylvania, United States
- Yerlikaya, Esma I., Penn State College of Medicine, Hershey, Pennsylvania, United States
- Dennis, Michael D., Penn State College of Medicine, Hershey, Pennsylvania, United States
Background
Diabetic nephropathy (DN) results in chronic loss of kidney function and is the leading cause of end-stage renal disease. Hyperglycemia is a key mediator of DN pathophysiology; promoting oxidative stress and inflammation associated injury. Presently, much remains unknown regarding the molecular events that contribute to chronic inflammation in the context of DN. Herein, we investigated the hypothesis that hyperglycemia-induced expression of the stress response protein REDD1 acts to exacerbate renal inflammation in response to the diabetes.
Methods
Wild-type (WT) and REDD1 knockout (KO) mice were administered streptozotocin to induce diabetes. Kidneys were isolated after 16 weeks of diabetes and analyzed for protein and RNA expression. Urinary albumin and creatinine levels were determined. Kidneys were fixed and renal sections were examined by immunofluorescence labeling. Similar analyses were performed on human podocyte cultures. GSK3β inhibition was carried out using VP3.15. Activation of the transcription factor nuclear factor kappa B (NF-κB) was assayed using a luciferase-based assay.
Results
REDD1 expression in the kidney of diabetic mice correlated with albuminuria and renal hypertrophy. Diabetes induction also increased NF-κB activation, pro-inflammatory gene transcript and IL-1β cytokine expression in the kidney of diabetic wild-type mice. In contrast, REDD1 KO mice failed to exhibit a diabetes-induced renal inflammatory response. Macrophage infiltration was observed in kidneys of diabetic WT mice but not in diabetic REDD1 KO mice. In cultured human podocytes, exposure to hyperglycemic conditions elevated REDD1 expression concomitant with increased inflammatory signaling. Pro-inflammatory gene transcript expression and IL1β release were not observed in podocyte cultures upon REDD1 deletion. Prior studies support that REDD1 acts via an Akt-GSK3β signaling axis. Indeed, inhibition of GSK3β prevented NF-κB mediated inflammation and reduced podocyte apoptosis associated renal injury in diabetic mice.
Conclusion
These findings provide new insights into how diabetes contributes to development of renal inflammation and support the possibility that therapeutics targeting REDD1 could be beneficial in the context of DN.
Funding
- Other NIH Support