Combined knockout of collecting duct endothelin A and B receptors causes hypertension and sodium retention.
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.
Ge
Yuqiang
Y
Division of Nephrology, Univ. of Utah Health Sciences Center, 1900 East, 30 North, Salt Lake City, UT 84132, USA.
Bagnall
Alan
A
Stricklett
Peter K
PK
Webb
David
D
Kotelevtsev
Yuri
Y
Kohan
Donald E
DE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004231:Diuresis; D005091:Exons; D017353:Gene Deletion; D006973:Hypertension / Q000235:genetics*; D007685:Kidney Tubules, Collecting / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D011188:Potassium / Q000097:blood / Q000652:urine; D044022:Receptor, Endothelin A / Q000172:deficiency* / Q000235:genetics; D044023:Receptor, Endothelin B / Q000172:deficiency* / Q000235:genetics; D012964:Sodium / Q000097:blood* / Q000494:pharmacology / Q000652:urine; D013599:Systole / Q000187:drug effects; D015431:Weight Loss
D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012964:Sodium; D011188:Potassium
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