TUBULOINTERSTITIAL INJURY WAS SUPPRESSED BY INHIBITION OF PLATELET-DERIVED GROWTH FACTOR PATHWAY IN RAT RENAL VENOUS CONGESTION MODEL

Abstract

Objective: Increased central venous pressure in congestive heart failure is responsible for renal dysfunction. Pericytes contribute to the renal myofibroblast pool in renal fibrogenesis via pericyte-myofibroblast transition (PMT), and their detachment of from capillaries might trigger capillary rarefaction. We recently created a novel rat renal congestion model by ligation of the inferior vena cava (IVC) between the renal veins, resulting high renal interstitial hydrostatic pressure, tubulointerstitial injury and PMT. In this model, platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated. Thus we examined the effect of imatinib, a PDGFR inhibitor, for renal injury. Design and method: The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion only in the left kidney. Imatinib mesylate (20 mg/kg) or saline were injected intraperitoneally every day from one day before the operation. Both the right control kidney and the left congested kidney were obtained 3 days after the surgery and were weighted. The expression of renal injury marker and PDGFRs were assessed by quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemistry. The vascular structure of the kidneys was observed using micro-computed tomography (μCT) and low-vacuum scanning electron microscopy (LV-SEM). Results: Kidney weight was significantly increased in the left congested kidneys, and ameliorated by imatinib administration. However, μCT and LV-SEM results showed the maintained congestive state even in imatinib administration. Renal injury and fibrosis were observed in the congested kidneys, and imatinib significantly suppressed renal injury and fibrosis around the vasa recta. Conclusions: These results suggest that the inhibition of the PDGFRs pathway could suppress the renal fibrosis after PMT in heart failure-derived renal congestion. This mechanism could be a candidate therapeutic target for renoprotection against heart failure.