Nephroprotective effects and antioxidant mechanisms of a novel polysaccharide from <em>Poria cocos</em> sclerotia in chemotherapy-induced kidney injury

Kidney injury is one of the common side effects in cancer patients receiving chemotherapy. Enhancement of renal antioxidant and anti-inflammation function are important strategies to combat chemotherapy-induced kidney injury. In this study, we successfully isolated a novel water-soluble polysaccharide (PCP, Mw: 55.245 kDa) from <em>Poria cocos</em> sclerotia, which features an α-1,4-D-Glcp backbone with branches linked at the O-6 positions. <em>In vitro</em>, PCP significantly relieved oxidative damage and apoptosis caused by the chemotherapeutic agent cisplatin in renal tubular epithelial cells (RTECs). <em>In vivo</em>, pretreatment with PCP attenuated cisplatin-induced kidney injury by mitigating oxidative stress, apoptosis, and inflammation. Furthermore, post-treatment with PCP facilitated the recovery of renal function following kidney injury. In chronic kidney injury model, PCP exhibited a persistent nephroprotective effect in inhibiting the progression of chronic kidney disease and fibrosis. Mechanistically, PCP protected RTECs from cisplatin by activating the Nrf2 signaling pathway. Importantly, PKCζ was identified as the upstream kinase responsible for initiating the phosphorylation activation of Nrf2. Taken together, PCP confers protection against cisplatin-induced kidney injury by activating the PKCζ-Nrf2 signaling pathway, suggesting that PCP may be a promising clinical candidate for the treatment of chemotherapy-induced kidney injury.