Chronic hyperglycemia, oxidative stress, and mitochondrial dysfunction are central drivers of renal structural and functional alterations associated with metabolic disease and accelerated tissue aging. In type 2 diabetes mellitus (T2DM), these mechanisms contribute to early kidney injury and progressive decline in renal resilience. Dietary interventions, including the Mediterranean diet (MD), have been proposed as complementary strategies to counteract metabolic stress, yet mechanistic evidence at the renal mitochondrial level remains limited.

Male db/db mice, a model of obesity- and diabetes-associated metabolic stress, were fed for 8 weeks a standard diet (SD), a Western diet (WD), or a lab-designed MD-based food mix. Db/m littermates on SD served as controls. Renal function, morphology, and molecular pathways related to mitochondrial homeostasis, oxidative stress, and tissue remodeling were assessed through metabolic profiling, histological evaluation, and protein expression analyses.

Db/db mice displayed overt metabolic dysfunction with increased glucosuria, polyuria, and water intake. SD- and WD-fed db/db animals showed a significant increase in urinary albumin-to-creatinine ratio (uACR), whereas MD-fed db/db mice maintained uACR at control levels, together with preserved serum creatinine and potassium. Histological analyses revealed attenuation of tubular hydropic changes and prevention of glomerular hypertrophy and hypercellularity under MD. At the molecular level, MD preserved nephrin expression, prevented diabetes-induced increases in NOX2, RAGE, and nitrotyrosine, and maintained mitochondrial dynamics by preserving the fission/fusion balance. Moreover, MD limited alterations in autophagy/mitophagy markers and reduced profibrotic (MT-MMP1, TIMP2) and hypoxia-related (HIF1α, VEGF) signaling.

A balanced MD-based dietary mix preserves renal structure and function in db/db mice by counteracting oxidative stress, mitochondrial dysfunction, and early fibrotic remodeling. These findings support the MD as a potential nutritional strategy to enhance renal resilience and mitigate metabolic stress–induced kidney aging in the context of diabetes and obesity.