Exploring the nephroprotective effects of combined finerenone and exenatide therapy in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a progressive complication of type 2 diabetes mellitus (T2DM) and a major cause of end-stage renal disease. Oxidative stress, inflammation, and dysregulated signaling pathways play critical roles in its pathogenesis. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, and exenatide, a GLP-1 receptor agonist, are known for their renoprotective, anti-inflammatory, and antioxidant properties. This study aimed to evaluate the combined effects of these agents in a rat model of DN. METHODS: Forty adult male Wistar rats were randomly divided into five groups: control, STZ-induced diabetic, STZ + finerenone, STZ + exenatide, and STZ + finerenone+exenatide. Diabetes was induced using streptozotocin (50 mg/kg). Treatments were administered for 21 days. Renal function was evaluated via serum urea, creatinine, and eGFR. Histological assessments included H&E, PAS, and Masson's trichrome staining. Inflammatory gene expression (TNF-α, IL-6, IL-1β, CCL2, CX3CL1, CX3CR1) was measured by qPCR. Protein expressions of p-STAT3, p-AKT, and p-NRF2 were analyzed by Western blotting. Oxidative stress markers (TAS, TOS, OSI) were also determined. RESULTS: The STZ group exhibited significant renal injury, increased inflammatory markers, and oxidative stress. Both finerenone and exenatide significantly improved histopathological and biochemical outcomes. This combination produced enhanced effects compared to monotherapies by reducing glomerular damage, inflammatory gene expression, and oxidative stress, while promoting NRF2 activation. CONCLUSIONS: The combined administration of finerenone and exenatide demonstrated potent nephroprotective effects in DN by attenuating inflammation and oxidative damage via modulation of NF-κB, PI3K/Akt/mTOR, and NRF2 pathways. These findings support the therapeutic potential of this combination for DN management.