Rosamultin from Potentilla anserine L. exhibits nephroprotection and antioxidant activity by regulating the reactive oxygen species/C/EBP homologous protein signaling pathway

Rosamultin, a major bioactive constituent from Potentilla anserine L., has antioxidative and hepatoprotective activities. However, its protective effects on cisplatin-induced acute renal injury and the underlying mechanisms remain elusive. In this work, rosamultin could enhance the viability of HEK293 cells treated by cisplatin. In vivo experiment showed that rosamultin effectively decreased kidney index, reduced blood urea nitrogen level, decreased urinary protein excretion, and ameliorated the histopathological damage and fibrosis of renal tissue induced by cisplatin. Besides, rosamultin showed no obvious toxicity in mice. SILAC-based quantitative proteomic analysis identified 4,461 proteins and eight proteins including C/EBP homologous protein (CHOP) were markedly decreased in cisplatin-treated HEK293 cells when exposed to rosamultin. Biochemical experiments further discovered that rosamultin could inhibit p38 and JNK activation, and downregulate the levels of CHOP and proteins in its upstream PERK-eIF2 alpha-ATF4 signaling pathway stimulated by cisplatin or tunicamycin. At the same time, rosamultin reduced the generation of intracellular ROS induced by cisplatin and enhanced the activities of antioxidant enzymes such as SOD, GSH, and CAT. Moreover, rosamultin markedly suppressed the expression of CHOP, apoptosis-associated proteins, and activation of p38 and JNK in renal tissue. These findings suggest that rosamultin might be a potential protectant against cisplatin-induced nephrotoxicity.