Nafamostat mesilate attenuates renal fibrosis by suppressing the IL-17 signaling pathway

Weili Liao¹Rui Fan²Yuman Du²Hairong Wang²Yong Yang¹Yuan Tian^2*

• ¹Mudanjiang Medical University, Mudanjiang, China
• ²Yangtze University Jingzhou Hospital, Jingzhou, China

Chronic kidney disease (CKD) is a global public health concern characterized by progressive renal function decline and fibrosis, ultimately leading to end-stage renal disease (ESRD). Renal tubular injury and renal interstitial fibrosis are key contributor to this process. Granzyme B (GZMB), a serine protease, has been studied for its role in inducing apoptosis during immune defense. However, the role of GZMB in tubular injury and renal interstitial fibrosis remain unclear. We found that GZMB was significantly upregulated in injured kidney tissues and damaged tubular epithelial cells. The administration of GZMB induced cells damage, inflammatory response, and partial epithelial to mesenchymal transition (p-EMT) within HK-2 cells. We also found the increase of perforin in fibrotic kidneys. GZMB caused tubular epithelial cell death in perforin-dependent and independent way. Additionally, we treated unilateral ischemia-reperfusion injury (UIRI) mice with Namumostat mesylate (NM), a broad-spectrum serine protease inhibitor which is used for anticoagulation during hemodialysis in the clinic. The results revealed that NM decreased serum creatinine, and alleviated tubular injury, renal interstitial fibrosis of UIRI mice. Mechanistically, NM inhibited the activation of IL-17/c-Fos signaling. In conclusion, these findings indicate that GZMB could serve as a novel therapeutic target for CKD, and the fundings of NM in the kidney provides a potential drug option for the clinical treatment of CKD.