Background/Aims: SIRT1 activation promotes the resistance of renal tubular cells to oxidative stress, and resveratrol is known as a SIRT1 activator. Methods: Resveratrol was injected intraperitoneally with iohexol for 24 hours. NRK-52E cells were pretreated with resveratrol for 24 hours and then exposed to iohexol for 3 hours. Renal function was measured by serum creatinine and cell survival was assessed by MTT assay. We investigated whether resveratrol attenuates oxidative stress and apoptosis in contrast-induced nephropathy (CIN). Results: Serum creatinine and tubular injury increased significantly after iohexol treatment, and resveratrol co-treatment attenuated the renal injury. Cell survival decreased after iohexol exposure and resveratrol reduced cell death induced by iohexol. Resveratrol was accompanied with the activation of SIRT1 and PGC-1α and dephosphorylation of FoxO1 in mice with CIN. SIRT1 and PGC-1α expression were decreased by iohexol, and increased significantly in resveratrol-pretreated cells. These processes resulted in reduction of oxidative stress and apoptosis both in vivo and in vitro experiments. Resveratrol decreased inflammatory cell infiltration induced by iohexol in mice with CIN. SIRT1 inhibition using siRNA in tubular cells accentuated the decrease of cell viability by iohexol. Conclusion: Resveratrol attenuated CIN by modulating renal oxidative stress and apoptosis through activation of SIRT1-PGC-1α-FoxO1 signaling.
Radiocontrast-induced nephropathy (CIN) is the third most common cause of acute renal failure. The pathophysiology of CIN is related to tubular injury caused by oxidative stress, and nuclear factor erythroid-2-related factor 2 (Nrf2) is critical in coordinating intracellular antioxidative processes. We thus investigated the role of Nrf2 in CIN. CIN was established in mice and in NRK-52E cells via iohexol administration according to the protocols of previous studies. To determine the role of Nrf2 in CIN, Nrf2 expression was reduced in vivo using Nrf2 knockout (KO) mice (B6.129 × 1-Nfe2 l2tm1Ywk/J) and in vitro with siRNA treatment targeting Nrf2. Increased Nrf2 expression was observed after iohexol treatment both in vivo and in vitro . Serum creatinine at 24 h after iohexol injection was significantly higher in KO mice than in wild-type (WT) mice. Histologic examination showed that iohexol-induced tubular vacuolization and structural disruption were aggravated in Nrf2 KO mice. Significant increases in apoptosis and F4/80(+) inflammatory cell infiltration were demonstrated in KO mice compared to WT mice. In addition, the increase in reactive oxygen species after iohexol treatment was augmented by Nrf2 inhibition both in vivo and in vitro . Nrf2 may be implicated in the pathogenesis of CIN via the modulation of antioxidant, anti-apoptotic, and anti-inflammatory processes.
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