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Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension.

Abstract
The present study was performed to assess the effects of the platelet-derived growth factor (PDGF) receptor kinase inhibitor imatinib mesylate on the renal morphological changes occurring during the development of malignant hypertension in transgenic rats with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Arterial blood pressure was measured by radiotelemetry in male Cyp1a1-Ren2 rats during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.3%) for 14 days to induce malignant hypertension. Rats induced with I3C (n = 5) had higher mean arterial pressures (178 ± 4 vs. 109 ± 2 mmHg, P < 0.001) and increased urinary albumin excretion (Ualb; 13 ± 5 vs. 0.6 ± 0.2 mg/day) compared with noninduced rats (n = 5). Chronic administration of imatinib (60 mg·kg(-1)·day(-1) in drinking water, n = 5) did not alter the magnitude of the hypertension (176 ± 8 mmHg) but prevented the increase in Ualb (1.6 ± 0.3 mg/day). Quantitative analysis of proliferating cell nuclear antigen using immunohistochemistry demonstrated increased proliferating cell number in cortical tubules (38 ± 5 vs. 18 ± 1 cells/mm(2)) and cortical interstitium (40 ± 7 vs. 13 ± 6 cells/mm(2)) of hypertensive rat kidneys. Renal cortical fibrosis evaluated by picrosirius red staining showed increased collagen deposition in kidneys of the hypertensive rats (1.6 ± 0.1 vs. 0.4 ± 0.1% of cortical area). Imatinib attenuated the increase in proliferating cell number in cortical tubules and interstitium (22 ± 5 vs. 38 ± 5 and 22 ± 6 vs. 40 ± 7 cells/mm(2), respectively) and reduced the degree of collagen deposition (0.8 ± 0.2 vs. 1.6 ± 0.1%) in the kidneys of hypertensive rats. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats involve activation of PDGF receptor kinase.
AuthorsMiguel L Graciano, Kenneth D Mitchell
JournalAmerican journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 302 Issue 1 Pg. F60-9 (Jan 01 2012) ISSN: 1522-1466 [Electronic] United States
PMID21975872 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Benzamides
  • Indoles
  • Piperazines
  • Pyrimidines
  • Ren2 protein, rat
  • Angiotensin II
  • Imatinib Mesylate
  • indole-3-carbinol
  • Cytochrome P-450 CYP1A1
  • PDGF receptor tyrosine kinase
  • Receptors, Platelet-Derived Growth Factor
  • Renin
Topics
  • Albuminuria (etiology, prevention & control)
  • Angiotensin II (physiology)
  • Animals
  • Benzamides
  • Cytochrome P-450 CYP1A1 (genetics)
  • Hypertension, Malignant (drug therapy, pathology, physiopathology)
  • Imatinib Mesylate
  • Indoles
  • Kidney (drug effects)
  • Male
  • Piperazines (therapeutic use)
  • Pyrimidines (therapeutic use)
  • Rats
  • Rats, Transgenic
  • Receptors, Platelet-Derived Growth Factor (metabolism)
  • Renin (genetics)

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