Abstract 15115: CXCR4 Antagonism Attenuates the Development of Hypertension and Inhibits Cardiorenal Fibrosis in Mineralocorticoid Excess
Introduction: Activation of the renin-angiotensin-aldosterone system (RAAS) contributes broadly to the development of cardiovascular disease including hypertension, ventricular remodelling and renal fibrosis. Stimulation of the RAAS is known to initiate an inflammatory response, including T lymphocyte accumulation, in hypertension and recent evidence shows that that an angiotensin-II mediated increase in SDF-1 (stromal derived factor 1) may contribute to cardiac fibrosis. We aimed to investigate the hypothesis that selective antagonism of the SDF-1 receptor, CXCR4, would attenuate the development of both hypertension and the accompanying cardiac and renal fibrosis.
Methods and Results: Hypertension, cardiac and renal fibrosis was induced by 6 weeks DOCA (deoxycorticosterone) in unilaterally nephrectomised (UNx) mice. Compared to control UNx DOCA treated mice showed elevated blood pressure, which was accompanied by left ventricular hypertrophy, with cardiac and renal fibrosis (Table). Addition of the CXCR4 antagonist AMD3465 (6mg/kg/d via minipump) markedly blunted the development of DOCA-induced hypertension, with significantly reduced both renal cardiac fibrosis (Table). Real time PCR analysis demonstrated elevated increased (p<0.05) expression of collagen type I and III mRNA in heart and kidney with DOCA and this was abrogated with CXCR4 antagonism.
Conclusions: Our data indicate that the SDF-1/CXCR4 axis plays a central role in the pathogenesis of hypertension and cardiorenal injury in RAAS induced hypertension. *p<0.05 vs UNx; † p<0.05 vs DOCA
- © 2010 by American Heart Association, Inc.