Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension

Physiological Reports

Nirupama Ramkumar¹  Deborah Stuart¹  Matias Calquin¹  Shuping Wang¹  Fumio Niimura²  Taiji Matsusaka² 

[1] Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;Institute of Medical Science, Tokai University, Isehara, Japan

关键词: Angiotensinogen;    blood pressure;    kidney;    liver;   

DOI  :  10.14814/phy2.12675

来源: Wiley

【 摘 要 】

Abstract

The role of intranephron angiotensinogen (AGT) in blood pressure (BP) regulation is not fully understood. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, whereas proximal tubule-specific deletion of AGT did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP-flanked AGT alleles to achieve nephron-wide AGT disruption after doxycycline induction. Compared to controls, AGT knockout (KO) mice demonstrated markedly reduced renal AGT immunostaining, mRNA, and protein levels; unexpectedly AGT KO mice had reduced AGT mRNA levels in the liver along with 50% reduction in plasma AGT levels. BP was significantly lower in the AGT KO mice compared to controls fed a normal, low, or high Na⁺ intake, with the highest BP reduction on a low Na⁺ diet. Regardless of Na⁺ intake, AGT KO mice had higher plasma renin concentration (PRC) and markedly reduced urinary AGT levels compared to controls. Following angiotensin-II (Ang-II) infusion, AGT KO mice demonstrated an attenuated hypertensive response despite similar suppression of PRC in the two groups. Taken together, these data suggest that nephron-derived AGT may be involved in Ang-II-dependent hypertension, however, a clear role for nephron-derived AGT in physiological BP regulation remains to be determined.

【 授权许可】

CC BY   
© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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