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

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 complet...

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Autores principales: Ramkumar, Nirupama, Stuart, Deborah, Calquin, Matias, Wang, Shuping, Niimura, Fumio, Matsusaka, Taiji, Kohan, Donald E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760401/
https://www.ncbi.nlm.nih.gov/pubmed/26755736
http://dx.doi.org/10.14814/phy2.12675
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author Ramkumar, Nirupama
Stuart, Deborah
Calquin, Matias
Wang, Shuping
Niimura, Fumio
Matsusaka, Taiji
Kohan, Donald E.
author_facet Ramkumar, Nirupama
Stuart, Deborah
Calquin, Matias
Wang, Shuping
Niimura, Fumio
Matsusaka, Taiji
Kohan, Donald E.
author_sort Ramkumar, Nirupama
collection PubMed
description 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.
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spelling pubmed-47604012016-02-22 Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension Ramkumar, Nirupama Stuart, Deborah Calquin, Matias Wang, Shuping Niimura, Fumio Matsusaka, Taiji Kohan, Donald E. Physiol Rep Original Research 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. John Wiley and Sons Inc. 2016-01-12 /pmc/articles/PMC4760401/ /pubmed/26755736 http://dx.doi.org/10.14814/phy2.12675 Text en © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Ramkumar, Nirupama
Stuart, Deborah
Calquin, Matias
Wang, Shuping
Niimura, Fumio
Matsusaka, Taiji
Kohan, Donald E.
Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension
title Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension
title_full Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension
title_fullStr Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension
title_full_unstemmed Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension
title_short Possible role for nephron‐derived angiotensinogen in angiotensin‐II dependent hypertension
title_sort possible role for nephron‐derived angiotensinogen in angiotensin‐ii dependent hypertension
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760401/
https://www.ncbi.nlm.nih.gov/pubmed/26755736
http://dx.doi.org/10.14814/phy2.12675
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