1371-P: REDD1 Induction in Podocytes Drives Mitochondrial Stress-Induced Ferroptosis in Diabetic Kidney Disease

Introduction and Objective: Ferroptosis is an emerging contributor to the pathogenesis of diabetic nephropathy (DN). We previously showed that podocyte-specific expression of the stress protein REDD1 is required for podocyte injury and filtration defects in diabetic mice. The studies here examined the role of diabetes-induced REDD1 in podocytes in mitochondrial dysfunction, ferroptosis, and renal damage. Methods: REDD1fl/fl and podocyte-specific REDD1 knockout mice (REDD1fl/fl;NPHS2-Cre) were fed a high fat diet to induce diabetes. Biochemical analyses and pathology was determined after 18 weeks of diet. Podocyte-specific REDD1 suppression was carried out in 12-week-old male mice homozygous for the diabetes spontaneous mutation (db/db) and heterozygous (db/+) controls by systemic shREDD1-AAV administration. Urine, serum, and kidney tissue were collected 4 weeks after intervention and analyzed. Similar analyses were also carried out in wild-type or REDD1-deficient human podocyte cultures exposed to media containing 150 µM palmitate. Results: RNA sequencing indicated palmitate-induced ferroptosis in cultured podocytes that was REDD1-dependent. REDD1 was also required for reduced mitochondrial respiration and increased mitochondrial stress concomitant with increased iron accumulation and ferroptotic cell death in podocytes exposed to hyperlipidemic conditions. Podocyte-specific REDD1 deletion prevented diabetes-induced albuminuria, glomerular ferroptosis, and podocyte loss. Importantly, therapeutic suppression of REDD1 specifically in podocytes attenuated podocyte injury and stemmed the progression of renal pathology and dysfunction in diabetic mice. Conclusion: Overall, the findings support the role of REDD1 in podocyte injury and dysfunction caused by diabetes and suggest the possibility that therapeutics targeting podocyte REDD1 could be beneficial in stemming the progression of DN. Disclosure S. Sunilkumar: None. M.D. Dennis: None. Funding American Diabetes Association (11-23-PDF-84), Children's Miracle Network (289625)