Open Medicine Journal

ISSN: 1874-2203 ― Volume 7, 2020

Inhibition of Renal Fibrosis and Glomerular Injury by Sacubitril/Valsartan, a Combination Angiotensin Receptor Blocker and Neprilysin Inhibitor, in a Salt-Sensitive Hypertensive Model Using Angiotensin 1 Receptor Knockout Mice: The Contribution of Non-Angiotensin Blocking Effects to Renal Protection

Rei Otsu1, Yoshiaki Taniyama1, 2, *, Fumihiro Sanada1, Jun Muratsu1, 2, Kana Shibata1, Tatsuya Fujikawa1, Kanako May Brule1, Hideo Shimizu1, Hiromi Rakugi2, Ryuichi Morishita1
1 Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
2 Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan



“Aldosterone breakthrough,” which is observed in patients receiving long term treatment with angiotensin blockade, is strongly associated with the increased risk of a declining glomerular filtration rate through the profibrotic actions of aldosterone. Sacubitril/valsartan is a newly created combination medicine (the angiotensin receptor blocker valsartan and the neprilysin-inhibitor sacubitril). Therefore, sacubitril/valsartan should have additional organ-protective actions besides the angiotensin blockade.


In this study, we examined the renal protective effect of sacubitril/valsartan in a salt-sensitive hypertension model using angiotensin II type 1a receptor (AT1aR) knockout mice. An oral administration of 1% NaCl solution with sacubitril/valsartan (30 or 60 mg/kg/day) or valsartan (15 or 30 mg/kg/day) alone beginning 7 days before administration of aldosterone was examined in an aldosterone infusion AT1R knockout mouse model as an aldosterone breakthrough model.

Results / Conclusion:

A significant decrease in Blood Pressure (BP) was observed in the sacubitril/valsartan group compared to the valsartan group under low and high doses. In addition, the pathological analysis of the kidney for glomerular fibrosis by Sirius red staining and for injury by PAS staining demonstrated significant reductions accompanied by a significant reduction in TGF-β in the sacubitril/valsartan group compared to the valsartan group. Overall, sacubitril/valsartan, which has the dual actions of the AT1R blockade and neprilysin inhibition, may have additional clinical values for the treatment of hypertensive patients with aldosterone breakthrough.

Keywords: Aldosterone breakthrough, Sacubitril/valsartan, Chronic kidney disease, Renal fibrosis, Glomerular injury, Angiotensin.

Article Information

Identifiers and Pagination:

Year: 2018
Volume: 5
First Page: 108
Last Page: 118
Publisher Id: MEDJ-5-108
DOI: 10.2174/1874220301805010108

Article History:

Received Date: 19/10/2018
Revision Received Date: 17/11/2018
Acceptance Date: 20/11/2018
Electronic publication date: 28/12/2018
Collection year: 2018

© 2018 Otsu et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan, Tel: +81-6-6210-8351, Fax: +81-6-6210-8359, E-mail

Track Your Manuscript:


"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."

Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."

Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."

Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."

Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."

Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."

Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."

Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."

J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."

Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."

Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."

Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."

Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."

Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."

M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."

Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."

Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."

Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."

Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."

Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."

Jih Ru Hwu
(National Central University, Taiwan)

Browse Contents

Webmaster Contact:
Copyright © 2020 Bentham Open