SUN-186 IMATINIB ATTENUATES PERYCITE-MYOFIBROBLAST TRANSITION IN RENAL CONGESTION IN RATS.

Abstract

Some reports have demonstrated that central venous pressure (CVP) is an indicator of both renal dysfunction and congestive heart failure, and increased CVP raises renal venous pressure (RVP), which leads to renal congestion and renal dysfunction. We have recently reported about pathophysiological and molecular mechanisms in renal congestion in a novel rat model (Sci Rep, in press). In that study, we demonstrated that increase in inferior vena cava (IVC) pressure induces a reduction of renal blood flow together with renal interstitial hydrostatic pressure, and hypoxia and physical stress induce pericyte detachment and podocyte injury. We could suggest that pericyte detachment induced by renal congestion activates Platelet-Derived Growth Factor (PDGFR), one of tyrosine kinase receptors, which was the main factor in extracellular matrix expansion. Here we report the efficacy of Imatinib, a PDGFR inhibitor, to renal fibrosis and podocyte injury in rat renal congestion model. All rats (Male Sprague-Dawly rats, 7 to 9 weeks) were anesthetized before surgery. The IVC between the renal veins was ligated. Each rat was given Imatinib Mesylate (50mg/kg) orally 2 hours before and every 12 hours after surgery. The control group were given the same amount of water. Three days after surgery, the IVC pressure was measured and the urine samples were collected separately from each kidney, and then the renal tissues were removed under anesthisia. Both kidneys were immediately sectioned and fixed for histological analyses, and then divided into the cortex and medulla for RNA analyses. Formalin-fixed renal paraffin-embedded renal tissues were undergone immunostaining of Transgelin (Tagln), Pdgfra, Pdgfrb as perycite-myofibroblast transision (PMT) markers, and Desmin as a podocyte marker, and Kidney injury molecule 1 (Kim1) as a renal proximal tubule injury marker. Total RNA extracted from the renal cortex and medulla underwent quantitative PCR (qPCR) for Tagln, Pdgfra, Pdgfrb, Desmin, Kim1. The relative mRNA expression levels were normalized by glyceraldehyde-3-phosphate dehydrogenase (Gapdh). Staining intensity and mRNA expression levels of Tagln, Pdgfra, Pdgfrb were higher in the control kidneys, especially in the cortex. Imatinib attenuated the intensity and mRNA expression levels. Desmin staining was higher in the control kidneys and imatinib lowered the intensity. On the other hand, as for Kim1, staining intensity showed no significant difference between the groups and mRNA expression level was elevated in an imatinib group. Podocyte and tubular injury occurred in rat renal congestion model together with pericyte detachment, which leads to renal fibrosis. Activation of PDGFRs was detected and Imatinib attenuates the elevation of PMT markers. These results may suggest that imatinib has some potentiality against renal fibrosis in renal congestion.