β-Sitosterol attenuates gentamicin-induced nephrotoxicity via ADAM-17/ACE2/Ang 1-7/MasR Axis modulation in rats

Gentamicin (Genta) is a widely used aminoglycoside antibiotic, but its clinical value is limited by nephrotoxicity involving oxidative stress, inflammation, apoptosis, and dysregulation of the ADAM-17/ACE2/Ang (1-7)/MasR axis. β-Sitosterol (BSST) is a phytosterol with reported antioxidant and anti-inflammatory properties, yet its nephroprotective activity and mechanistic link to this signaling pathway have not been explored. This study investigated whether BSST mitigates Genta-induced renal injury in association with modulation of this axis together with autophagy and apoptotic pathways.

Male Wistar rats were assigned to five groups: control, BSST (40 mg/kg), Genta (100 mg/kg), and Genta combined with BSST (20 or 40 mg/kg). Renal function markers, oxidative stress indices, ELISA-based quantification of ADAM-17, ACE2, Ang (1-7), Ang II, and Cystatin-C, Western blot analyses of FOXO-1, LC3-II, P62, p38, and NF-κB, qRT-PCR for MasR, ATG5, TNF-α, and IL-6, histopathology, and caspase-3 immunostaining were performed.

Genta significantly increased serum creatinine, BUN, uric acid, Cystatin-C, renal MDA, ADAM-17, Ang II, NF-κB, and p38, while decreasing GSH, ACE2, Ang (1-7), LC3-II, ATG5, and MasR (P < 0.05). BSST co-treatment attenuated these alterations in a dose-dependent manner and markedly reduced renal apoptosis and tissue damage. The 40 mg/kg BSST dose produced the most pronounced effects.

This study provides novel evidence that BSST protects against Genta-induced nephrotoxicity with findings consistent with restoring the ADAM-17/ACE2/Ang (1-7)/MasR balance, suppressing oxidative and inflammatory responses, re-establishing autophagy, and reducing apoptosis. BSST may represent a promising nephroprotective adjunct during aminoglycoside therapy.