REDD1 expression in podocytes facilitates renal inflammation and pyroptosis in streptozotocin-induced diabetic nephropathy
Year: 2025
Type: article
Abstract: Sterile inflammation resulting in an altered immune response is a key determinant of renal injury in diabetic nephropathy (DN). In this investigation, we evaluated the hypothesis that hyperglycemic 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). In support of the hypothesis, streptozotocin (STZ)-induced diabetes increased REDD1 protein abundance in the kidney concomitant with renal immune cell infiltration. In diabetic mice, administration of the SGLT2 inhibitor dapagliflozin reduced blood glucose concentrations, renal REDD1 protein abundance, and immune cell infiltration. In contrast with diabetic REDD1+/+ mice, diabetic REDD1-/- mice did not exhibit albuminuria, increased pro-inflammatory factors, or renal macrophage infiltration. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1-dependent activation of NF-κB signaling. Suppression of REDD1 in podocytes reduced cytokine and chemokine expression and attenuated macrophage chemotaxis in response to hyperglycemic conditions. Notably, podocyte-specific REDD1 deletion prevented the pro-inflammatory immune cell infiltration in the kidneys of diabetic mice. Furthermore, exposure of podocytes to hyperglycemic conditions promoted REDD1-dependent pyroptotic cell death, evidenced by an NLRP3-mediated increase in caspase-1 activity and LDH release. REDD1 expression in podocytes was also required for an increase in pyroptosis markers in the glomeruli of diabetic mice. The data support that podocyte-specific REDD1 is necessary for chronic NF-κB activation in the context of diabetes and raises the prospect that therapies targeting podocyte-specific REDD1 may be helpful in DN.
Source: Cell Death and Disease
Institution: Pennsylvania State University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,990
Funders: American Diabetes Association, BrightFocus Foundation, University of Pennsylvania, Pennsylvania State University, Juvenile Diabetes Research Foundation United Kingdom, Children's Miracle Network Hospitals, University of Bristol, National Institutes of Health, Penn State College of Medicine, National Eye Institute, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W4407246160