Z-Guggulsterone alleviates renal fibrosis by mitigating G2/M cycle arrest through Klotho/p53 signaling

Chronic kidney disease (CKD) has become a major public health problem worldwide. Renal fibrosis is considered to be the final outcome and potential therapeutic target of CKD. Z-Guggulsterone (Z-GS), an active compound derived from Commiphora mukul, has been proved to be effective in various diseases. The present study was aimed to evaluate the effect and mechanism of Z-GS on renal fibrosis. Unilateral ureteral obstruction (UUO) mice and hypoxia-induced HK-2 cells were used to simulate renal fibrosis, respectively. The mice and cells were treated with different doses of Z-GS to observe the pharmacological action. Results demonstrated that Z-GS lightened renal function and histopathological injury induced by UUO. Z-GS also alleviated renal fibrosis in mice by inhibiting the expressions of α-SMA, TGF-β, and Collagen Ⅳ. Besides, Z-GS delayed G2/M cycle arrest by promoting the expressions of CDK1 and CyclinB1. Experiments in vitro indicated that Z-GS increased cell viability while decreased LDH release in hypoxia-induced HK-2 cells. In addition, fibrosis and G2/M cycle arrest induced by hypoxia in HK-2 cells were retarded by Z-GS. The study of its possible mechanism exhibited that Z-GS increased the level of Klotho and inhibited p53 level. Nevertheless, the effect of Z-GS on Klotho/p53 signaling was reversed by siRNA-Klotho. Moreover, siRNA-Klotho eliminated the effects of Z-GS on G2/M cycle arrest and fibrosis. Taken together, this study clarified that Z-GS alleviated renal fibrosis and G2/M cycle arrest through Klotho/p53 signaling. People who have suffered CKD may potentially benefit from treatment with Z-GS.