School of Medicine
55 Loss of Soluble (Pro)Renin Receptor Attenuates Kidney Injury and Fibrosis in Unilateral Ureteral Obstruction
Dhruvan Gopinath and Nirupama Ramkumar
Faculty Mentor: Nirupama Ramkumar (Internal Medicine, University of Utah)
Abstract
The prorenin receptor (PRR) is a recently discovered component of the Renin-Angiotensin-Aldosterone System (RAAS) that is involved in the maintenance of kidney function and blood pressure. Cleavage of the extracellular domain of the (pro)renin receptor yields a soluble fragment termed soluble PRR (sPRR). We previously demonstrated that loss of sPRR attenuates angiotensin-II-induced hypertension and kidney injury. To further characterize the role of sPRR in chronic kidney disease and fibrosis, we used an experimental model known as unilateral ureteral obstruction (UUO) to induce kidney disease in male wild type and mutant mice with loss of sPRR. UUO surgery was performed, and mice were followed for 3-day or 7-day time periods. Markers of kidney injury, fibrosis, and kidney inflammation were examined by qRT-PCR and kidney fibrosis by Picro Sirius Red staining. Our results showed that 1) UUO mice had markedly increased expression of markers of kidney injury, inflammation and fibrosis compared to Sham at 3 and 7 days following UUO; 2) loss of sPRR attenuated gene expression of fibronectin and Monocyte Chemoattractant Protein-I (MCP-I) with a trend toward lower expression of Kidney Injury Molecule-1 (KIM-1), Collagen-I (COL-I) and Vascular Cell Adhesion Molecule-I (VCAM-I), compared to WT UUO mice; 3) no differences were observed in expression of Tumor Necrosis Factor (TNF-α), Transforming Growth Factor Beta (TGF-β), and Interleukin-6 (IL6) between WT and mutant mice that underwent UUO; 4) At 7 days following UUO, all markers were similar between WT and mutant UUO mice. Additionally, Sirius Red staining showed reduced fibrosis in mutant UUO mice compared to WT UUO mice. Thus, loss of sPRR had acute kidney protective effects in UUO at 3 days but not 7 days. Further studies are needed to examine the effect of sPRR in kidney disease and fibrosis.
Keywords: soluble (pro)renin receptor, kidney injury, fibrosis, chronic kidney disease
Introduction
Chronic kidney disease (CKD) has emerged as a leading cause of death in the 21st century (Kovesdy, 2022). Estimates show that as many as 843 million individuals are affected by CKD stages 1-5 worldwide. This is largely in part due to an increased prevalence of risk factors such as obesity, diabetes, and hypertension. Additionally, moderate to severe CKD patients have greatly increased mortality, primarily due to cardiovascular disease (CVD) (Jankowski et al., 2021). Between 40-50% of Stage 4 and End Stage Renal Disease (ESRD) patients result in cardiovascular mortality, thus, improved treatment of CKD can reduce the prevalence of CVD. C KD is defined as the presence of kidney damage or loss of estimated glomerular filtrate rate (GFR) of <60 mL/min per 1.73 m2 for mo