Involvement of Calcium (Ca)-Sensing Receptor in the Development of Interstitial Fibrosis

Background: The function of the calcium-sensing receptor (CaSR) in the kidney have not been well understood. We previously reported that the expression of CaSR significantly decreases with the progression of renal interstitial fibrosis. In this study, we administered etelcalcetide (ETL), a CaSR agonist, to a renal fibrosis model to analyze the relationship between CaSR and renal fibrosis. Methods: We created a renal fibrosis model using 8-week-old Sprague-Dawley rats with unilateral ureteral obstruction (UUO). The rats were sacrificed on the seventh day after ureteral ligation, and samples were collected. Some UUO rats were subcutaneously administered ETL at a dose of 0.5 mg/kg/day. The rats were divided into three groups: Sham (n=8), UUO (n=9), and UUO+ETL (n=10). We conducted blood biochemical tests, evaluated fibrosis using ED-1 staining, αSMA staining, Azan staining, and Picro-Sirius Red (PSR) staining, and compared mRNA expression levels of molecules related to fibrosis, repair, and regeneration using RT-PCR. Results: CaSR expression significantly decreased due to UUO, but immunohistochemistry and mRNA expression analysis confirmed partial recovery of CaSR expression with ETL administration. Azan staining and PSR staining demonstrated a significant reduction in fibrosis with ETL treatment in UUO rats. ED-1 and αSMA staining revealed a significant decrease in positive areas with ETL administration. Furthermore, ETL treatment significantly increased BMP-7 mRNA expression compared to the UUO group. Conclusion: ETL partially restored reduced CaSR expression in the kidney, improved renal fibrosis, and inhibited the accumulation of extracellular matrix. The involvement of BMP-7 suggests that CaSR agonists could be a novel therapeutic approach for inhibiting renal fibrosis.