Risedronate attenuates renal fibrosis by targeting prenylation-dependent RhoA/ROCK1 and ERK/NF-κB signaling

Chronic kidney disease (CKD) is a global health concern with rising morbidity and mortality. The repurposing of drugs offers a valuable opportunity to accelerate therapeutic development in CKD. Risedronate (RIS), a nitrogen-containing bisphosphonate approved to prevent and treat bone-related conditions, has therapeutic potential in CKD. Hence, we aimed to investigate the potential of RIS in unilateral ureteral obstruction (UUO)-induced renal fibrosis in Sprague-Dawley (SD) rats and recombinant human-transforming growth factor-β1 (rh-TGF-β1)-induced fibrosis in normal rat kidney epithelial cells (NRK-52E). Following randomization, animals were subjected to sham, UUO, and UUO + RIS (5 µg/kg, s.c., twice weekly) for 21 days. Post-treatment, plasma, urine, and kidney tissue samples were collected for subsequent biochemical, histological, and immunohistochemical analysis. Additionally, NRK-52E cells were divided into a normal control (NC), rh-TGF-β1, and rh-TGF-β1 + RIS (10 µM) groups for 48 h, and cell samples were harvested for cell viability, cell morphology, and immunocytochemistry assay. RIS treatment notably restored the kidney mass ratio and kidney function parameters, and histopathological studies showed that RIS significantly preserved the kidney structure in UUO rats. While RIS treatment notably suppresses the levels of FPPS, p-NF-κB, TNF-α, IL-6, TGF-β, and CTGF, as well as collagen and fibronectin, as proven by immunohistochemistry, ELISA, and qRT-PCR in UUO rats. Moreover, immunocytochemistry suggested that RIS inhibits protein prenylation-dependent expression of p-ERK 1/2, RhoA, and ROCK1 in NRK-52E cells. Indeed, the study findings indicated that RIS treatment modulated renal fibrosis by targeting prenylation-dependent RhoA/ROCK1 and ERK/NF-κB signaling axis, holding the clinical promise in CKD management.