PDGF Receptor Antagonism Prevents the Increase in Urinary Angiotensin II Excretion in Cyp1a1‐Ren2 Transgenic Rats with Angiotensin II‐Dependent Malignant Hypertension

Abstract

The present study was performed to determine if chronic administration of the PDGF receptor antagonist, imatinib mesylate, prevents the augmentation of urinary ANG II excretion that occurs in Cyp1a1‐Ren2 transgenic rats with ANG II‐dependent malignant hypertension. Male Cyp1a1‐Ren2 rats (n=6/group) were induced to develop malignant hypertension by dietary administration of indole‐3‐carbinol (I3C, 0.3% wt/wt) for 10 days. One group was chronically treated with imatinib mesylate by oral gavage (60 mg/kg/d) starting 3 days before initiating I3C induction and maintained on imatinib for the duration of the study. Systolic blood pressures (SBP) were measured daily by tail‐cuff plethysmography. Rats were placed in metabolic cages for measurement of 24‐hour urine output and urinary protein and ANG II excretion. Dietary I3C resulted in pronounced increases in SBP (152±6 to 209±6 mmHg, P<0.001) and urine output (8.5±0.7 to 60±5 ml/day, P<0.001), marked proteinuria (26.8±3.0 to 72.2±11.8 mg/day, P<0.01), and augmented urinary ANG II excretion (448±12 to 987±119 fmol/hr, P<0.05). Chronic imatinib administration did not prevent the development of hypertension (204±3 vs. 157±8 mmHg, P<0.001) or the increase in urine flow (61.8±5.0 vs. 8.5±0.6 ml/day, P<0.001), but prevented the I3C‐induced increases in proteinuria (21.8±2.2 vs. 21.8±0.8 mg/day) and urinary ANG II excretion (263±30 vs. 492±43 fmol/hr). The present findings demonstrate that PDGF receptor antagonism with imatinib mesylate prevents the marked 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.