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

Area of Science:

• Nephrology
• Pharmacology
• Biochemistry

Background:

• Chronic kidney disease (CKD) is a significant global health issue with increasing prevalence and mortality.
• Drug repurposing offers a viable strategy to expedite the development of novel therapeutics for CKD.
• Risedronate (RIS), a bisphosphonate used for bone conditions, exhibits potential therapeutic benefits in managing CKD.

Purpose of the Study:

• To investigate the efficacy of Risedronate (RIS) in mitigating renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats.
• To explore the effects of RIS on transforming growth factor-β1 (TGF-β1)-induced fibrosis in normal rat kidney epithelial cells (NRK-52E).

Main Methods:

• Adult Sprague-Dawley rats underwent sham surgery, UUO, or UUO with RIS treatment for 21 days.
• Biochemical, histological, and immunohistochemical analyses were performed on plasma, urine, and kidney tissue samples.
• NRK-52E cells were treated with TGF-β1 with or without RIS to assess cell viability, morphology, and protein expression via immunocytochemistry.

Main Results:

• RIS treatment improved kidney function and preserved kidney structure in UUO rats, as evidenced by restored kidney mass ratio and histopathology.
• RIS significantly suppressed the expression of fibrosis markers including FPPS, p-NF-κB, TNF-α, IL-6, TGF-β, CTGF, collagen, and fibronectin.
• In NRK-52E cells, RIS inhibited protein prenylation-dependent expression of p-ERK 1/2, RhoA, and ROCK1.

Conclusions:

• Risedronate (RIS) effectively modulates renal fibrosis in a preclinical model of CKD.
• RIS targets the prenylation-dependent RhoA/ROCK1 and ERK/NF-κB signaling pathways to exert its renoprotective effects.
• These findings suggest that RIS holds significant clinical promise for the management of chronic kidney disease.