Editors' ChoiceHypertension

Minimizing the Mischief of Mineralocorticoids

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Science Translational Medicine  03 Aug 2011:
Vol. 3, Issue 94, pp. 94ec120
DOI: 10.1126/scitranslmed.3002962

More than 70 million people in the United States are hypertensive, and high blood pressure continues to be a vexing public health problem. Elucidating the mechanisms leading to hypertension and cardiovascular disease is challenging because so many factors have been implicated. Fibrosis is a common tissue response to hypertension and can occur in both the heart and kidneys. Mineralocorticoids, which under normal physiological conditions maintain the balance of salt and water, are known to contribute to hypertension. These hormones may also have an important role in promoting vascular and tissue inflammation, which in turn contributes to fibrosis of the heart and kidneys. In a new study, Chu et al. working in a mouse model examine whether blocking a receptor involved in inflammation, CXCR4, could attenuate cardiorenal fibrosis resulting from excess mineralocorticoids. CXCR4 binds to stromal derived factor-1 (SDF-1), a chemotactic protein that regulates the migration of lymphocytes, fibrocytoid cells, and hematopoietic stem cells.

Six-week-old male mice underwent unilateral nephrectomy and were subsequently implanted with either a 60-day slow-release pellet of mineralocorticoids or a placebo pellet. Mice were then randomized to receive a CXCR4 antagonist. The animals were killed 6 weeks later. Mice exposed to the mineralocorticoids had markedly increased blood pressure and heart and kidney weights as compared with those of control animals that received the placebo. Administration of the CXCR4 antagonist to mineralocorticoid-treated mice reduced their blood pressure and heart weight but did not affect the blood pressure of mice receiving placebo. Histological examination revealed that mice receiving mineralocorticoids had extensive fibrosis of the kidney and of the heart’s left ventricle, which could be attenuated by the CXCR4 antagonist. Those mice exposed to mineralocorticoids accumulated lymphocytes in their myocardium and kidneys, and this accumulation was reduced by administration of the CXCR4 antagonist.

This study contributes to accumulating evidence that blockade of the CXCR4/SDF-1 signaling pathway in the setting of mineralocorticoid excess may be an important target for reducing hypertension and associated heart disease.

P.-Y. Chu et al., CSCR antagonism attenuates the cardiorenal consequences of mineralcorticoid excess. Circ. Heart Fail. 17 June 2011 (10.1161/CIRCHEARTFAILURE.110.960831). [Abstract]

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