Extrarenal ETB plays a significant role in controlling cardiovascular responses to high dietary sodium in rats.
Endothelin-B receptor (ET(B))-deficient rats have low-renin, salt-sensitive hypertension. We hypothesized this was caused by an absence of renal ET(B) signaling and performed a series of experiments to examine the effect of dietary sodium (Na) on endothelin-1 (ET1) expression and renal function in wild-type (WT) and ET(B)-deficient rats. We found that ET(B) deficiency, but not dietary Na, increases circulating and tissue (kidney and aorta) ET1 levels. Quantitative reverse-transcription polymerase chain reaction reveals that aortic and renal ET1 and endothelin-A receptor (ET(A)) mRNA, however, are similarly increased by dietary Na in ET(B)-WT and ET(B)-deficient rats. We then determined the effect of chronic ET(A) blockade on blood pressure (direct conscious measurements), urinary protein excretion, and creatinine clearance (Crcl). On a Na-deficient diet, ET(B)-deficient rats have mild proteinuria and impaired Crcl. On a high-Na diet, severe hypertension and renal dysfunction develop in ET(B)-deficient rats. Chronic ET(A) blockade prevents hypertension and renal injury. To determine the role of the renal versus the extrarenal endothelin system, we performed renal cross-transplantation. We found that ET(B) deficiency in the body is associated with renal injury and an impaired ability to excrete an Na load. We also found that ET(B) deficiency in the body affects blood pressure response to dietary Na. Expression of ET1 and ET(A) are regulated by dietary Na. ET(B) receptors outside of the kidney, likely by functioning as a clearance receptor for ET1, limit salt-sensitivity in rats.
Ohkita
Mamoru
M
Department of Pediatrics, University of Michigan, Ann Arbor 48109-0656, USA.
Wang
Yuqin
Y
Nguyen
Ngoc Diep T
ND
Tsai
Yu-Hwai
YH
Williams
S Clay
SC
Wiseman
Richard C
RC
Killen
Paul D
PD
Li
Shujun
S
Yanagisawa
Masashi
M
Gariepy
Cheryl E
CE
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006085:Graft Survival; D006973:Hypertension / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology; D016030:Kidney Transplantation; D008297:Male; D009318:Natriuresis; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A / Q000235:genetics; D044023:Receptor, Endothelin B / Q000172:deficiency / Q000502:physiology*; D012982:Sodium, Dietary / Q000008:administration & dosage* / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000503:physiopathology
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012982:Sodium, Dietary