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Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome

AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI o...

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Autores principales: Tsukamoto, Shunichiro, Wakui, Hiromichi, Uehara, Tatsuki, Shiba, Yuka, Azushima, Kengo, Abe, Eriko, Tanaka, Shohei, Taguchi, Shinya, Hirota, Keigo, Urate, Shingo, Suzuki, Toru, Yamada, Takayuki, Kinguchi, Sho, Yamashita, Akio, Tamura, Kouichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630100/
https://www.ncbi.nlm.nih.gov/pubmed/37941728
http://dx.doi.org/10.1093/ehjopen/oead098
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author Tsukamoto, Shunichiro
Wakui, Hiromichi
Uehara, Tatsuki
Shiba, Yuka
Azushima, Kengo
Abe, Eriko
Tanaka, Shohei
Taguchi, Shinya
Hirota, Keigo
Urate, Shingo
Suzuki, Toru
Yamada, Takayuki
Kinguchi, Sho
Yamashita, Akio
Tamura, Kouichi
author_facet Tsukamoto, Shunichiro
Wakui, Hiromichi
Uehara, Tatsuki
Shiba, Yuka
Azushima, Kengo
Abe, Eriko
Tanaka, Shohei
Taguchi, Shinya
Hirota, Keigo
Urate, Shingo
Suzuki, Toru
Yamada, Takayuki
Kinguchi, Sho
Yamashita, Akio
Tamura, Kouichi
author_sort Tsukamoto, Shunichiro
collection PubMed
description AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. METHODS AND RESULTS: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. CONCLUSION: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.
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spelling pubmed-106301002023-11-08 Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome Tsukamoto, Shunichiro Wakui, Hiromichi Uehara, Tatsuki Shiba, Yuka Azushima, Kengo Abe, Eriko Tanaka, Shohei Taguchi, Shinya Hirota, Keigo Urate, Shingo Suzuki, Toru Yamada, Takayuki Kinguchi, Sho Yamashita, Akio Tamura, Kouichi Eur Heart J Open Original Article AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. METHODS AND RESULTS: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. CONCLUSION: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria. Oxford University Press 2023-09-29 /pmc/articles/PMC10630100/ /pubmed/37941728 http://dx.doi.org/10.1093/ehjopen/oead098 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Tsukamoto, Shunichiro
Wakui, Hiromichi
Uehara, Tatsuki
Shiba, Yuka
Azushima, Kengo
Abe, Eriko
Tanaka, Shohei
Taguchi, Shinya
Hirota, Keigo
Urate, Shingo
Suzuki, Toru
Yamada, Takayuki
Kinguchi, Sho
Yamashita, Akio
Tamura, Kouichi
Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
title Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
title_full Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
title_fullStr Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
title_full_unstemmed Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
title_short Combination of sacubitril/valsartan and blockade of the PI3K pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
title_sort combination of sacubitril/valsartan and blockade of the pi3k pathway enhanced kidney protection in a mouse model of cardiorenal syndrome
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630100/
https://www.ncbi.nlm.nih.gov/pubmed/37941728
http://dx.doi.org/10.1093/ehjopen/oead098
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