Oleanolic acid attenuates cisplatin-induced nephrotoxicity in mice through regulation of multiple signaling pathways

Oleanolic acid (OA) is a natural triterpenoid that possesses numerous beneficial health effects such as antioxidant, antiinflammatory, and anti-apoptotic activities. However, the renoprotective effect of OA in cisplatin (CP)-intoxicated mice is unknown. In this study we investigated the effect of OA on CP-induced nephrotoxicity. Treatment with OA ameliorated the increased serum markers and histological features of kidney injury. Also, CP administration increased renal expression of oxidative stress markers HO-1 and 4-HNE as well as the expression of proinflammatory cytokine TNF-α and NF-κB, which was reduced by OA administration, indicating the inhibition of oxidative stress and inflammation. Likewise, an increased expression of caspase-3/9 with concomitant increase in PARP cleavage suggested CP-induced apoptosis in the kidneys. OA exhibited anti-apoptotic activity by decreasing the expression of stated markers. Treatment with OA also ameliorated LC3B-II and Atg5 expression induced by CP, indicating the anti-autophagic activity of OA. Mechanistically, CP administration resulted in upregulation of ERK1/2, STAT3, and NF-κB but OA dose- dependently alleviated their activation. Our results suggest that OA ameliorates CP-induced oxidative stress, inflammation, apoptosis, and autophagy in mice kidneys and its nephroprotective activity could be attributed to the downregulation of multiple signaling pathways.