Resveratrol protects human renal proximal tubular cells from high glucose and hypoxia/reoxygenation induced injury via inhibiting p38-MAPK and thioredoxin-interacting protein (TXNIP) pathways

Patients with diabetes are more susceptible to acute kidney injury (AKI), but the underlying mechanisms and therapeutic strategies remain unclear. Much evidence suggests that tubular cells apoptosis induced by oxidative stress and inflammatory reaction is involved in diabetes and AKI. The aim of the present study was to determine the mechanism of hyperglycemia related susceptibility of ischemic AKI and to examine whether resveratrol (RES) could attenuate cell injury induced by high glucose and hypoxia/reoxygenation (HH/R) via p38-MAPK/TXNIP signaling. Human renal proximal tubular cells (HK-2 cells), cultured in high glucose (HG: 30 mM) for 72 hours with or without RES (50 mu M) pretreatment, were subjected to hypoxia/reoxygenation (H/R) in the presence or absence of TXNIP and p38-MAPK achieved by gene knock-down with VDUP-1 (TXNIP) siRNA and SB203580, as a selective inhibitor of p38-MAPK. The protein expression of p-p38-MAPK and TXNIP in HK-2 cells exposed to HG and H/R insult were significantly increased, accompanied with severe cell injury, oxidative stress and inflammatory reaction, and elevated the level of cell apoptosis. All these changes were attenuated or reversed by RES treatment, and similar effects were shown in the treatment group by inhibition of TXNIP with VDUP-1 (TXNIP) siRNA or with SB203580. Our results suggest that the protective effects of RES may be achieved through inhibition of p38-MAPK activation and expression of TXINP in HK-2 cells exposed to HG and H/R insult. Thus, the RES could be a candidate for inhibiting ischemia-reperfusion induced AKI in diabetes.