The antioxidative effect of oligomeric procyanidins on neutrophil extracellular traps alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis

Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited susceptible neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. Under the dual stimulation of intestinal bacteria and cisplatin, neutrophils become extremely susceptible to form Neutrophil extracellular traps (NETs), accumulating in the proximal tubule and promoted chronic inflammation, fibrosis, and chronic hypoxia, leading to poor regeneration that promoted CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggered local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon– γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPCs) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPCs ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPCs altered the susceptibility of neutrophils to form NETs. In summary, OPC alleviates CKD by inhibiting NETs production via TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney through anti-inflammatory and antioxidant activities, and restore the balance of the intestinal flora.