Resveratrol exerts dose-dependent anti-fibrotic or pro-fibrotic effects in kidneys: A potential risk to individuals with impaired kidney function

Renal fibrosis is the pathological feature of chronic kidney disease (CKD) which leads to end-stage renal disease (ESRD) and renal failure. Resveratrol [3,5,4'-trihydroxy-trans-stilbene (RSV)] has shown benefits for metabolic diseases and anti-cancer therapy, but its potential risk on renal health has not been fully evaluated.To investigate the global effects of RSV on renal fibrosis in human tubular epithelial cell (TEC) line HK-2, and in mice with unilateral ureteral obstruction (UUO).A TGF-β-induced in vitro model of epithelial-mesenchymal transition (EMT) in TEC was established. The effects of RSV on cell viability, pro-fibrotic factors, oxidative stress, mitochondria function, and underlying pathway proteins were analyzed. In vivo, the effects of RSV on renal function and fibrosis were assayed in UUO mice.Our results showed that low concentrations of RSV (5-20 μM) decreased TGF-β-induced EMT via Sirt1-dependent deacetylation of Smad3/Smad4 mechanism. By contrast, long-term (72 h) exposure to high concentrations of RSV (≥ 40 μM) promoted EMT in HK-2 cells via mitochondrial oxidative stress and ROCK1-mediated disordered cytoskeleton remodeling. In vivo, low-dose treatment of RSV (≤ 25 mg/kg) partly improved renal function, whereas high-dose treatment of RSV (≥ 50 mg/kg) lost its anti-fibrotic role and even aggravated renal fibrosis. However, mice with UUO were more susceptible to high RSV-induced renal injury than normal mice.Dependent on dose, RSV activated either anti-fibrotic or pro-fibrotic effects in kidneys. The risk of RSV consumption in individuals with impaired kidney function should be carefully considered.