Introduction and Objective: Innate immune signaling is a key driver of diabetic nephropathy (DN). We previously showed that diabetes-induced expression of the stress protein REDD1 contributes to proinflammatory signaling in podocytes. The objective of this study was to determine if therapeutic suppression of REDD1 in podocytes was sufficient to mitigate renal inflammation in diabetic mice.Methods: Podocyte-specific REDD1 suppression was carried out in 12-week-old male mice homozygous for the diabetes spontaneous mutation (db/db) and heterozygous (db/+) by systemic shREDD1-AAV administration. Spot urine albumin and creatinine levels, and serum creatinine and blood urea nitrogen (BUN) levels were assayed. Kidneys were removed after 4 weeks of intervention and analyzed for immune cell infiltrates using flow cytometry. Protein and mRNA expression in isolated glomeruli were determined. RNA sequencing was carried out in wild-type or REDD1-deficient human podocyte cultures exposed to media containing 150 µM palmitate.Results: In cultured human podocytes exposed to hyperlipidemic conditions, the cGAS-STING pathway was activated in a REDD1-dependent manner. In db/db mice, glomerular STING activation was increased concomitant with pro-inflammatory immune cell infiltration into the kidney. Podocyte-specific REDD1 knockdown attenuated the activation of cGAS-STING signaling and reduced the innate immune response in the kidney of diabetic mice. Most notably, REDD1 suppression halted the progression of podocyte loss, aberrant glomerular pathology, and renal dysfunction in diabetic mice.Conclusion: Overall, the findings support the possibility that therapeutics targeting podocyte REDD1 are beneficial in suppressing innate immune response activation in DN.
S. Sunilkumar: None. S. Moothedath Subrahmanian: None. M.D. Dennis: None.
American Diabetes Association (11-23-PDF-84), Children’s Miracle Network (289625)
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