SAT-188 EXPRESSION OF (PRO)RENIN RECEPTOR IN RAT RENAL CONGESTION MODEL

Abstract

The physiological association between the kidney and heart has received significant attention. Reduction of cardiac output induces renal hypoperfusion, which causes renal ischemia. On the other hand, renal venous hypertension leads to high renal interstitial hydrostatic pressure and reduction in glomerular filtration rate (GFR). In patients with chronic congestive heart failure, central venous pressure and renal venous pressure are higher than in healthy subjects, causing renal congestion and dysfunction. We have recently developed a novel rat renal congestion model, and reported its pathophysiological and molecular aspects. In this model, renal congestion reduced renal blood flow and GFR, and increased renal interstitial hydrostatic pressure, resulting renal fibrosis together with podocyte and tubular injury. Molecules related to extracellular matrix expansion, tubular injury and focal adhesion were upregulated. (Pro)renin receptor [(P)RR] is initially identified as a member of renin angiotensin system. (P)RR also functions in intracellular acidification (a part of vacuolar type H+-ATPase), and cell proliferation through Wnt signaling pathway. We have reported the inhibition of (P)RR and V-ATPase suppresses cellular fibrosis induced by TGF-β1 in peritoneal mesothelial cells. No study, however, have investigated the association between (P)RR and renal congestion. Thus, we assessed (P)RR expression in our rat renal congestion model. All animal experiments were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and were approved by animal experiment committees in Tohoku Medical and Pharmaceutical University and Tohoku University. The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats (7-9 weeks) to increase upstream IVC pressure and induce congestion in the left kidney only. Three days after surgery, both right control kidney and left congestive kidney were removed under anesthesia. The kidneys were immediately sectioned and fixed with 10% neutral-buffered formalin for histological analyses, and then divided into the cortex and medulla for RNA and protein analyses. mRNA expression of (P)RR and V-ATPase subunits was examined by quantitative real-time polymerase chain reaction. (P)RR protein expression was detected by western blot analysis and immunohistochemistry. mRNA expression levels of (P)RR and V-ATPase subunits (Atp6v0b, Atp6v0c, Atp6v1b1, Atp6v1b2 and Atp6v1c1) were significantly decreased in the congestive kidney, compared with the control kidney in both cortex and medulla. (P)RR protein was also decreased in the congestive kidney, especially in the medulla. By immunohistochemistry, (P)RR was highly expressed in the intercalated cells of the collecting ducts and weakly stained podocyte and other tubular segments in the control kidney, and the expression was abolished in the congestive kidney. Decrease of (P)RR and V-ATPase might relate to the progression of renal fibrosis in renal congestion.