Resveratrol Attenuates Exercise-induced Acute Kidney Injury by Inhibiting NLRP3 Inflammasome-mediated Renal Tubular Pyroptosis

Abstract

Abstract Background: Scholars have raised concerns that exercise-induced acute kidney injury (EAKI) could cause long-term renal damage and that new therapeutic strategies should be explored. Resveratrol is a natural agonist of silent mating-type information regulation 2 homolog 1 (SIRT1). Increasing lines of evidence in clinical and experimental animal models have confirmed the renal protective effect of resveratrol. However, the application of resveratrol against EAKI has not been fully revealed. Methods: A four-week treadmill running session was adopted to build an EAKI model in rats. The in vitro model was induced by bovine serum album (BSA) in HK-2 cells. The levels of renal function biomarkers (protein to creatinine ratio, albumin to creatinine ratio, serum creatinine, blood urea nitrogen) were detected by an automatic biochemical analyzer. H and E staining was used to evaluate the severity of renal injury. Western blot analysis and immunofluorescence staining were conducted to verify the expression of the NLRP3 inflammasome. Renal tubular injury markers (NGAL, KIM-1) and renal inflammatory factors (IL-1β, IL-18, TNF-α, IL-6) were evaluated by enzyme-linked immunosorbent assay. HK-2 cell pyroptosis was detected by Hochest33342/PI staining. Pharmacological interventionwith SIRT1 was performed to clarify its function in resveratrol-mediated effects. Results Results of protein expression and morphological analyses showed the occurrence of pyroptosis in the renal tubules of the EAKI rats. Resveratrol reduced not only post-exercise proteinuria but also the levels of pro-inflammatory cytokines in the kidneys after exhausting exercise. Resveratrol also inhibited the NLRP3-ASC-caspase1 inflammasome and pyroptosis. Mechanistically, resveratrol promoted SIRT1 expression and attenuated NF-κB activation. Inhibiting SIRT1 (by EX527) reversed resveratrol-mediated effects against renal injury and pyroptosis in HK-2 cells. Administration of resveratrol mitigated renal injury by suppressing inflammation and pyroptosis. Conclusion Resveratrol could attenuate exercise-induced renal injury by inhibiting NLRP3 inflammasome-mediated renal tubular pyroptosis.