Combination of α-Klotho and telmisartan attenuates diabetic kidney disease via mitigating EMT, inflammation and apoptosis.

Diabetic kidney disease (DKD) remains a leading cause of end-stage kidney disease worldwide, necessitating novel therapeutic approaches. This study investigated the renoprotective potential of recombinant human α-Klotho (α-Klotho; KL) as an adjunctive therapy to telmisartan (TEL) in streptozotocin-induced DKD rats and high glucose and exogenous TGF-β1 (rh-TGF-β1) -exposed NRK-52E cells. The combination therapy significantly preserved kidney function parameters, including reduced blood urea nitrogen, serum creatinine, and kidney weight/body weight ratio compared to monotherapy or untreated DKD groups. Histopathological analyses revealed that the combination therapy markedly ameliorated glomerular hypertrophy, tubular atrophy, and interstitial fibrosis as evidenced by H&E, PAS, and Masson's trichrome staining. Immunohistochemical evaluation demonstrated significant downregulation of AT1R and TGF-β1 expression in the combination group. In-vitro studies confirmed that co-treatment enhanced cell viability and preserved normal epithelial morphology of NRK-52E cells under high glucose conditions. Mechanistically, the combination therapy modulated the apoptotic pathway by upregulating Bcl-2 and downregulating Bax expression while simultaneously reducing phosphorylated NF-κB levels, suggesting suppression of inflammation-mediated tubular apoptosis. Additionally, the combination therapy effectively reduced extracellular matrix (ECM) deposition by decreasing fibronectin levels (ELISA) and collagen expressions (RT-PCR). Immunofluorescence analysis demonstrated reduced vimentin expression, indicating a lower degree of epithelial-mesenchymal transition (EMT), along with an increase in α-SMA levels in the animal tissues. These findings demonstrate that adjunctive α-Klotho therapy with telmisartan exerts synergistic renoprotective effects through anti-fibrotic, anti-inflammatory, and anti-apoptotic mechanisms. This combination approach represents a promising therapeutic strategy for DKD management that warrants further clinical investigation.