Abstract 559: Augmented Renal Levels of PDGFß And PDGFß Receptors in Cyp1a1-Ren2 Transgenic Rats With Angiotensin II-Dependent Malignant Hypertension

Abstract

PDGF receptor antagonism with imatinib mesylate prevents the renal injury, proteinuria and augmented urinary ANG II excretion independent of changes in blood pressure that occur in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. These findings suggest that arterial pressure-dependent increases in PDGFβ protein levels and PDGFβ receptor activation contribute importantly to the marked renal functional and morphological derangements that occur in ANG II-dependent malignant hypertension. To address this issue, the present study was performed to determine the protein levels of PDGFβ and PDGFβ receptors in renal cortical and medullary tissue from kidneys of hypertensive Cyp1a1-Ren2 transgenic rats. Male Cyp1a1-Ren2 rats were fed a diet containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension (n=5) or a non-I3C containing diet (controls, n=6). Rats induced with I3C developed malignant hypertension and exhibited increases in PDGFβ protein levels in both the renal cortex (0.046±0.002 vs.0.026±0.003 AU, P<0.05) and renal medulla (0.054±0.007 vs.0.026±0.003 AU, P<0.05), and elevated PDGFβ receptor levels in both renal cortex (0.26±0.03 vs.0.12±0.02 AU, P<0.05) and renal medulla (0.60±0.06 vs.0.21±0.02 AU, P<0.05). In a separate group (n=5), rats were chronically treated with the PDGF receptor antagonist, imatinib mesylate, by oral gavage (60 mg/kg/d) starting 3 days before initiating I3C induction and maintained on imatinib for the 10 day duration of I3C administration. Chronic PDGF receptor blockade prevented the increase in PDGFβ protein levels in both renal cortical and medullary tissues (0.027±0.004 vs. 0.026±0.003 and 0.029±0.005 vs. 0.026±0.003 AU, respectively) but did not influence the elevated PDGFβ receptor levels in either renal cortex (0.23±0.02 vs. 0.26±0.02 AU) or renal medulla (0.46±0.03 vs.0.60±0.06 AU). These data demonstrate that both PDGFβ protein and PDGFβ receptor levels are elevated in both renal cortex and medulla in ANG II-dependent malignant hypertension. Such elevated levels may contribute to the renal injury and the increased urinary ANG II excretion in ANG II-dependent malignant hypertension.