Simvastatin Mitigates Kidney Injury via Inhibition of the TNF-α/α-SMA Signaling Pathway in a Subtotal Nephrectomy Model.

OBJECTIVE: This study aims to investigate the preventive effect of simvastatin on the subtotal nephrectomy model by analysing key mediators of inflammation and fibrosis. METHODS: A total of 30 male Swiss mice were used in this study. The animals were divided into five groups (six/group): the sham group (Sham), the nephrectomy group (Neph), and three simvastatin groups (Simv) with a stepwise dose of simvastatin (5, 10, or 20 mg/kgBW). Kidney function was assessed by measuring serum creatinine, blood urea nitrogen (BUN), and proteinuria. Interstitial fibrosis was evaluated by Sirius red staining, α-SMA expression was evaluated by immunohistochemistry, and TNF-α expression was evaluated by real-time PCR. RESULTS: Subtotal nephrectomy significantly impaired renal function, increased interstitial fibrosis, and upregulated TNF-α and α-SMA expression. Simvastatin treatment dose-dependently reduced serum creatinine and proteinuria, although the reduction in BUN was not significantly different from the Neph group. Simvastatin also significantly attenuated interstitial fibrosis (8.62±2.43 in Simv5 group, 4.15±1.67 in Simv10, and 2.62±0.63 in Simv20 groups), decreased the expression of TNF-α (0.42±0.27 in Simv5, 0.39±0.18 in Simv10, and 0.23±0.21 in Simv20) and α-SMA (3.85±0.97 in Simv5, 2.74±0.61 in Simv10, and 1.59±0.45 in Simv20 groups) in dose-dependent manner, compared with the Neph group (all p < 0.05). Path analysis demonstrated that TNF-α indirectly contributed to renal fibrosis by promoting α-SMA expression, whereas α-SMA had a significant direct effect on interstitial fibrosis (p=0.038). CONCLUSION: This study found that the renoprotective effect of simvastatin in a subtotal nephrectomy model may be mediated by inhibition of the TNF-α/α-SMA signalling pathway, with α-SMA acting as a key mediator linking inflammation to renal fibrosis.