#3650 LINACLOTIDE IS PROTECTIVE AGAINST RENAL ISCHEMIA-REPERFUSION INJURY

Abstract Background and Aims Renal ischemia-reperfusion injury is associated with delayed graft function and poor long-term graft survival following transplantation. Linaclotide is a guanylate cyclase C (GC-C) receptor agonist that increases intracellular cGMP concentrations and promotes intestinal transport capacity by activating the GC-C receptor. Since CKD is a deficiency of cGMP in the kidney, increasing cGMP in the kidney by linaclotide would suppress fibrosis, protecting the kidney. Method An AKI rat model of unilateral nephrectomy plus contralateral ischaemia (30 min) and impaired reperfusion (up to 14 days) was used. Linaclotide was administered before and after surgery for 2 weeks, and blood and renal tissue samples were collected to determine its effect on renal function and whether it was protective against the progression of CKD. Results In the I/R injury+ group, creatinine levels were lower in the linaclotide-treated group than in the non-treated group. Sirius red staining showed significant improvement in fibrosis. The hydroxyproline content of kidneys was determined by the basic hydroxyproline method. RNA seq showed that genes down-regulated in I/R injury+ were the oxidative stress markers SOD3 and Gpx1. The expression of genes down-regulated in I/R injury+ was up-regulated to a degree similar to that in I/R injury- by treatment with linaclotide. These data suggest that linaclotide may ameliorate renal fibrosis by suppressing renal dysfunction through its antioxidant effects. Conclusion The antioxidant effect of linaclotide was found to suppress the decrease in renal function caused by I/R. We would like to apply this finding to human renal transplantation in the future to prevent renal function deterioration due to I/R.