ACS Pharmacol Transl Sci. 2025 Apr 16;8(5):1270-1281. doi: 10.1021/acsptsci.4c00552. eCollection 2025 May 9.
ABSTRACT
Inflammatory response, oxidative stress, and pyroptosis play important roles in the pathogenesis of diabetic kidney disease (DKD), and the NOD-like receptor protein 3 (NLRP3) inflammasome complex and pyroptosis are possible cellular regulators dependent on these processes. Treatment of DKD relies on sodium-glucose cotransporter-2 inhibitors (SGLT2is); however, its effects on oxidative stress and the NLRP3 complex have not yet been fully elucidated. This study aimed to evaluate the role of a SGLT2i in the regulation of the redox system, inflammatory profile, and NLRP3 inflammasome in an experimental model of DKD. Briefly, C57BL/6 mice were subjected to a DKD model induced by the combination of a high-caloric diet and streptozotocin (40 mg/kg). The animals were exposed to empagliflozin 35 mg/kg, and clinical (plasma glucose, water and caloric intake, and weight gain) and functional (glycosuria and albuminuria) parameters were subsequently evaluated. After 25 weeks, the animals were euthanized for evaluation of histological parameters, redox activity, NLRP3 complex activity, and pyroptosis. Our results showed that DKD model animals had clinical features of DKD, namely, high body mass index, glucose levels, albuminuria, and glomerular area. Empagliflozin reduced glycemia levels, glomerular area, H2O2 levels, IL-1β, IL-1α, and TNF-α levels, lipid peroxidation, and protein carbonylation. It also improved urinary albumin excretion and decreased gasdermin D levels. No changes were observed in the NLRP3 complex proteins. In conclusion, the SGLT2i empagliflozin improved glycemic control and reduced glomerular damage through control of the redox profile and inflammatory parameters, indicating its potential as a treatment for DKD.
PMID:40370980 | PMC:PMC12070321 | DOI:10.1021/acsptsci.4c00552