SGLT2 Inhibition Ameliorates Age-Dependent Renovascular Rarefaction

Introduction: Aging is associated with progressive loss of renal function and vascular structure, with and without chronic kidney disease. However, the mechanisms driving renal vascular aging and potential therapeutic interventions remain poorly understood. Methods: To model this state-of-affairs, we used African turquoise killifish (Nothobranchius furzeri), a naturally short-lived vertebrate. We then inhibited the sodium-glucose co-transporter 2 inhibition (SGLT2i) to test a potential therapeutic intervention. Histological, immunofluorescent, and 3D vascular imaging were used to evaluate glomerular, tubular, and vascular changes. Single-nuclei transcriptomic profiling was performed on whole kidneys to identify age- and treatment-associated molecular signatures. Results: Aged killifish kidneys exhibited hallmark features of human renal aging, including glomerulosclerosis, tubular fibrosis, and vascular rarefaction. Functional changes included increased proteinuria and altered tubular transporter expression. Transcriptomic profiling revealed a metabolic shift from oxidative phosphorylation to glycolysis and upregulation of pro-inflammatory pathways. Aged vasculature also displayed a marked reduction in tight junctions and cell–cell contacts. Dapagliflozin attenuated age-related vascular rarefaction, preserved functional peritubular capillary networks, and reduced albuminuria by restoring a youthful transcriptional profile and enhancing intercellular signaling. However, fish lifespan was not extended. Conclusion: This study establishes the killifish as a translational model for investigating renal vascular aging. We show that SGLT2i preserves renal microvascular structure and function, reduces proteinuria, and reprograms the aged transcriptome. These results support a vascular-protective role of SGLT2i in mitigating age-related renal deterioration. Comparison betweeen young and old (untreated) and old treated killifish. Old untreated animals serve as control of physiological aging. Treatment was performed using the sodium-glucose-linked transporter 2 (SGLT2) inhibitor dapagliflozin. Male and Female fish were examined. The data presented is a pooled sample of approximatly 4-9 fish.