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The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory sta...

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Autores principales: Figueroa, Stefanny M., Bertocchio, Jean-Philippe, Nakamura, Toshifumi, El-Moghrabi, Soumaya, Jaisser, Frédéric, Amador, Cristián A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223994/
https://www.ncbi.nlm.nih.gov/pubmed/37242615
http://dx.doi.org/10.3390/pharmaceutics15051373
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author Figueroa, Stefanny M.
Bertocchio, Jean-Philippe
Nakamura, Toshifumi
El-Moghrabi, Soumaya
Jaisser, Frédéric
Amador, Cristián A.
author_facet Figueroa, Stefanny M.
Bertocchio, Jean-Philippe
Nakamura, Toshifumi
El-Moghrabi, Soumaya
Jaisser, Frédéric
Amador, Cristián A.
author_sort Figueroa, Stefanny M.
collection PubMed
description Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells (SMC). In this study, we investigated whether MR is involved in the renal damage generated by Tac and if the MR expressed in SMC is involved. Littermate control mice and mice with targeted deletion of the MR in SMC (SMC-MR-KO) were administered Tac (10 mg/Kg/d) for 10 days. Tac increased the blood pressure, plasma creatinine, expression of the renal induction of the interleukin (IL)-6 mRNA, and expression of neutrophil gelatinase-associated lipocalin (NGAL) protein, a marker of tubular damage (p < 0.05). Our study revealed that co-administration of spironolactone, an MR antagonist, or the absence of MR in SMC-MR-KO mice mitigated most of the unwanted effects of Tac. These results enhance our understanding of the involvement of MR in SMC during the adverse reactions of Tac treatment. Our findings provided an opportunity to design future studies considering the MR antagonism in transplanted subjects.
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spelling pubmed-102239942023-05-28 The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice Figueroa, Stefanny M. Bertocchio, Jean-Philippe Nakamura, Toshifumi El-Moghrabi, Soumaya Jaisser, Frédéric Amador, Cristián A. Pharmaceutics Communication Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells (SMC). In this study, we investigated whether MR is involved in the renal damage generated by Tac and if the MR expressed in SMC is involved. Littermate control mice and mice with targeted deletion of the MR in SMC (SMC-MR-KO) were administered Tac (10 mg/Kg/d) for 10 days. Tac increased the blood pressure, plasma creatinine, expression of the renal induction of the interleukin (IL)-6 mRNA, and expression of neutrophil gelatinase-associated lipocalin (NGAL) protein, a marker of tubular damage (p < 0.05). Our study revealed that co-administration of spironolactone, an MR antagonist, or the absence of MR in SMC-MR-KO mice mitigated most of the unwanted effects of Tac. These results enhance our understanding of the involvement of MR in SMC during the adverse reactions of Tac treatment. Our findings provided an opportunity to design future studies considering the MR antagonism in transplanted subjects. MDPI 2023-04-29 /pmc/articles/PMC10223994/ /pubmed/37242615 http://dx.doi.org/10.3390/pharmaceutics15051373 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Figueroa, Stefanny M.
Bertocchio, Jean-Philippe
Nakamura, Toshifumi
El-Moghrabi, Soumaya
Jaisser, Frédéric
Amador, Cristián A.
The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
title The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
title_full The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
title_fullStr The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
title_full_unstemmed The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
title_short The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice
title_sort mineralocorticoid receptor on smooth muscle cells promotes tacrolimus-induced renal injury in mice
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223994/
https://www.ncbi.nlm.nih.gov/pubmed/37242615
http://dx.doi.org/10.3390/pharmaceutics15051373
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