Isorhapontigenin Modulates SOX9/TOLLIP Expression to Attenuate Cell Apoptosis and Oxidative Stress in Paraquat-Induced Acute Kidney Injury

Abstract

Paraquat (PQ) is a widely used herbicide but can be lethal to humans. The kidney is vital for PQ elimination; therefore, explorations for therapeutic approaches for PQ-induced acute kidney injury (AKI) are of great significance. Here, the effects of a natural bioactive polyphenol isorhapontigenin (ISO) on PQ-AKI were investigated. In vitro experiments carried out in PQ-intoxicated rat renal tubular epithelial cells (NRK-52E) showed that ISO treatment inhibited PQ-induced cell apoptosis and oxidative stress, which was evidenced by the decreased proapoptotic proteins [cleaved caspase 3/9 and poly (ADP-ribose) polymerase (PARP)], the reduced oxidative stress indicators [reactive oxygen species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) leakage], and the increased antioxidants [superoxide dismutase (SOD), nuclear factor E2-related factor 2 (NRF2), and oxygenase-1 (HO-1)]. Furthermore, 50 mg/kg ISO pretreatment before PQ administration significantly attenuated PQ-AKI in rats, as manifested by the improved renal tubule damage, the reduced serum and urine markers of kidney injury, and the inhibited cell apoptosis and oxidative stress in the renal cortex. Furthermore, expression of sex-determining region Y box 9 (SOX9) and Toll-interacting protein (TOLLIP) in NRK-52E cells and the renal cortex was significantly upregulated after ISO treatment. Overexpression of SOX9 increased TOLLIP transcription and attenuated PQ-induced apoptosis and oxidative stress, whereas knockdown of SOX9 impaired the protective effects of ISO on NRK-52E cells against PQ toxicity. In conclusion, the present study demonstrated that ISO modulated SOX9/TOLLIP expression to attenuate cell apoptosis and oxidative stress in PQ-AKI, suggesting the potential of ISO in treating PQ-poisoned patients.