The Protective Effect of Ursolic Acid on Unilateral Ureteral Obstruction in Rats by Activating the Nrf2/HO-1 Antioxidant Signaling Pathway

Abstract

Renal interstitial fibrosis is a common pathological feature of a variety of kidney diseases that progress to end-stage renal disease. The excessive deposition of extracellular matrix (ECM) is a typical pathological change of renal interstitial fibrosis. The production of reactive oxygen species in renal tubules is an important factor leading to the development of renal interstitial fibrosis. Ursolic acid (UA) is a natural pentacyclic triterpene carboxylic acid compound widely found in plants. It has anti-inflammatory, antioxidant, and antitumor cell proliferation effects. It can reduce the development of fibrosis by inhibiting the oxidative stress response of the liver; there is currently no relevant research on whether UA can protect the renal interstitial fibrosis by resisting oxidative stress in the kidneys. In this study, our purpose is to investigate the effect of ursolic acid on renal interstitial fibrosis after unilateral ureteral obstruction (UUO) in rats and its related mechanisms. We established a UUO model by surgically ligating the right ureter of the rat and instilling UA preparation (40 mg/kg/d) through the stomach after the operation, once a day for 7 days. We found that UUO caused impaired renal function, increased pathological damage, increased renal interstitial fibrosis, increased apoptosis, increased oxidative stress damage, and decreased antioxidants. However, after UA preparations were given, the abovementioned damage was significantly improved. At the same time, we also found that UA preparations can significantly increase the relative expression of Nrf2/HO-1 signaling pathway in kidney tissue after UUO. In order to further verify whether the Nrf2/HO-1 signaling pathway is involved in the development of renal interstitial fibrosis, we injected zinc protoporphyrin (ZnPP, 45 umol/kg), a specific blocker of the Nrf2/HO-1 signaling pathway, into the intraperitoneal cavity after UUO in rats and before the gastric perfusion of ursolic acid preparations. Subsequently, we observed that the protective effect of UA on renal interstitial fibrosis after UUO in rats was reversed. Combining all the research results, we proved that UA has a protective effect on renal interstitial fibrosis after UUO in rats, which may be achieved by activating the Nrf2/HO-1 signaling pathway.