Podocyte-specific Expression of the Stress Response Protein REDD1 is Required for Activation of the Renal Innate Immune Response and Pyroptosis in Diabetic Nephropathy

Diabetic nephropathy (DN) results in chronic loss of kidney function and is the leading cause of end-stage renal disease. Sterile inflammation resulting in an altered immune response is a key determinant of renal injury in DN. Presently, much remains unknown regarding the molecular events that contribute to chronic inflammation in the context of DN. In this investigation, we evaluated the hypothesis that diabetogenic conditions augment the pro-inflammatory immune response in the kidney by promoting podocyte-specific expression of the stress response protein regulated in development and DNA damage response 1 (REDD1). To test the hypothesis, REDD1 fl/fl and podocyte-specific NPHS2-cre REDD1 knockout (REDD1 podKO ) mice were administered low-dose streptozotocin (STZ) to induce diabetes. After 16 weeks of STZ-diabetes, increased REDD1 protein abundance colocalized with the podocyte marker nephrin in the kidney concomitant with albuminuria and renal immune cell infiltration in REDD1 fl/fl mice. Podocyte-specific REDD1 deletion attenuated albuminuria and reduced proinflammatory cytokine and chemokine expression in the kidneys of diabetic mice. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1-dependent activation of a GSK3β/NF-κB signaling axis. More specifically, both REDD1 and GSK3β were required for enhanced canonical NF-κB activation and macrophage chemotaxis under hyperglycemic conditions. Flow cytometry analysis showed that diabetes-induced infiltration of the pro-inflammatory macrophages (CD11b+F480+; CD86+ cells) was markedly attenuated in the kidneys of REDD1 podKO mice. Additionally, exposure of podocytes to hyperglycemic conditions promoted REDD1-dependent pyroptotic cell death, evidenced by an NLRP3 inflammasome-mediated increase in caspase-1 activity, Gasdermin D (GSDMD) cleavage, and LDH release. Importantly, STZ-diabetes-induced NLRP3 and GSDMD colocalized with nephrin in the kidneys of REDD1 fl/fl mice, but not REDD1 podKO mice. The data support that podocyte-specific REDD1 is necessary for the chronic renal inflammatory response in the context of diabetes and raises the prospect that therapies targeting podocyte-specific REDD1 could be beneficial in improving patient outcomes in DN. American Diabetes Association Grant#11-23-PDF-84 and Children's Miracle Network Trainee Award (to SS), and National Institutes of Health grant R01 EY032879 (to MDD). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.