Combined knockout of collecting duct endothelin A and B receptors causes hypertension and sodium retention

Sep 12, 2008American journal of physiology. Renal physiology

Removing both types of endothelin receptors in the kidney's collecting duct leads to high blood pressure and salt buildup

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Abstract

CD-specific knockout of both ETA and ETB receptors leads to increased blood pressure and reduced sodium excretion.

Knockout of ET-1 in the collecting duct causes hypertension, while knockout of the ETA receptor does not alter blood pressure.
Knockout of the ETB receptor increases blood pressure, but to a lesser extent than ET-1 knockout.
Mice with knockout of both ETA and ETB receptors excreted less urinary sodium during both acute and chronic sodium loading.
Despite similar urinary aldosterone and plasma renin levels, CD ETA/B knockout mice exhibited salt-sensitive hypertension.
Combined deficiency of CD ETA and ETB receptors results in a greater increase in blood pressure than the loss of either receptor alone.

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The collecting duct (CD) endothelin (ET) system regulates blood pressure (BP) and Na excretion. CD-specific knockout (KO) of ET-1 causes hypertension, CD-specific KO of the ETA receptor does not alter BP, while CD-specific KO of the ETB receptor increases BP to a lesser extent than CD ET-1 KO. These findings suggest a paracrine role for CD-derived ET-1; however, they do not exclude compensation for the loss of one ET receptor by the other. To examine this, mice with CD-specific KO of both ETA and ETB receptors were generated (CD ETA/B KO). CD ETA/B KO mice excreted less urinary Na than controls during acute or chronic Na loading. Urinary aldosterone excretion and plasma renin concentration were similar during Na intake and both fell comparably during Na loading. On a normal sodium diet, CD ETA/B KO mice had increased BP, which increased further with high salt intake. The degree of BP elevation during normal Na intake was similar to CD ET-1 KO mice and higher than CD ETB KO animals. During 1 wk of Na loading, CD ETA/B KO mice had higher BPs than CD ETB KO, while BP was less than CD ET-1 KOs until the latter days of Na loading. These studies suggest that 1) CD ETA/B deficiency causes salt-sensitive hypertension, 2) CD ETA/B KO-associated Na retention is associated with failure to suppress the renin-angiotensin-aldosterone system, and 3) CD ETA and ETB receptors exerts a combined hypotensive effect that exceeds that of either receptor alone.

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Combined knockout of collecting duct endothelin A and B receptors causes hypertension and sodium retention

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