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Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis

Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to...

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Autores principales: Jensen, Camilla Grønkjær, Jensen, Michael Schou, Tingskov, Stine Julie, Olinga, Peter, Nørregaard, Rikke, Mutsaers, Henricus A. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389588/
https://www.ncbi.nlm.nih.gov/pubmed/34440060
http://dx.doi.org/10.3390/biomedicines9080856
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author Jensen, Camilla Grønkjær
Jensen, Michael Schou
Tingskov, Stine Julie
Olinga, Peter
Nørregaard, Rikke
Mutsaers, Henricus A. M.
author_facet Jensen, Camilla Grønkjær
Jensen, Michael Schou
Tingskov, Stine Julie
Olinga, Peter
Nørregaard, Rikke
Mutsaers, Henricus A. M.
author_sort Jensen, Camilla Grønkjær
collection PubMed
description Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to the wide variety of comorbidities observed in these patients. To illustrate, catabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) gives rise to numerous biologically active metabolites implicated in CKD progression. Here, we evaluated the effect of antagonizing IDO on renal fibrogenesis. To this end, we antagonized IDO using 1-methyl-D-tryptophan (1-MT) and BMS-98620 in TGF-β-treated murine precision-cut kidney slices (mPCKS) and in mice subjected to unilateral ureteral obstruction (UUO). The fibrotic response was evaluated on both the gene and protein level using qPCR and western blotting. Our results demonstrated that treatment with 1-MT or BMS-985205 markedly reduced TGF-β-mediated fibrosis in mPCKS, as seen by a decreased expression of collagen type 1, fibronectin, and α-smooth muscle actin. Moreover, IDO protein expression clearly increased following UUO, however, treatment of UUO mice with either 1-MT or BMS-986205 did not significantly affect the gene and protein expression of the tested fibrosis markers. However, both inhibitors significantly reduced the renal deposition of collagen in UUO mice as shown by Sirius red and trichrome staining. In conclusion, this study demonstrates that IDO antagonism effectively mitigates fibrogenesis in mPCKS and reduces renal collagen accumulation in UUO mice. These findings warrant further research into the clinical application of IDO inhibitors for the treatment of renal fibrosis.
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spelling pubmed-83895882021-08-27 Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis Jensen, Camilla Grønkjær Jensen, Michael Schou Tingskov, Stine Julie Olinga, Peter Nørregaard, Rikke Mutsaers, Henricus A. M. Biomedicines Article Chronic kidney disease (CKD) is a major global health concern and renal fibrosis is an integral part of the pathophysiological mechanism underlying disease progression. In CKD patients, the majority of metabolic pathways are in disarray and perturbations in enzyme activity most likely contribute to the wide variety of comorbidities observed in these patients. To illustrate, catabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) gives rise to numerous biologically active metabolites implicated in CKD progression. Here, we evaluated the effect of antagonizing IDO on renal fibrogenesis. To this end, we antagonized IDO using 1-methyl-D-tryptophan (1-MT) and BMS-98620 in TGF-β-treated murine precision-cut kidney slices (mPCKS) and in mice subjected to unilateral ureteral obstruction (UUO). The fibrotic response was evaluated on both the gene and protein level using qPCR and western blotting. Our results demonstrated that treatment with 1-MT or BMS-985205 markedly reduced TGF-β-mediated fibrosis in mPCKS, as seen by a decreased expression of collagen type 1, fibronectin, and α-smooth muscle actin. Moreover, IDO protein expression clearly increased following UUO, however, treatment of UUO mice with either 1-MT or BMS-986205 did not significantly affect the gene and protein expression of the tested fibrosis markers. However, both inhibitors significantly reduced the renal deposition of collagen in UUO mice as shown by Sirius red and trichrome staining. In conclusion, this study demonstrates that IDO antagonism effectively mitigates fibrogenesis in mPCKS and reduces renal collagen accumulation in UUO mice. These findings warrant further research into the clinical application of IDO inhibitors for the treatment of renal fibrosis. MDPI 2021-07-22 /pmc/articles/PMC8389588/ /pubmed/34440060 http://dx.doi.org/10.3390/biomedicines9080856 Text en © 2021 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 Article
Jensen, Camilla Grønkjær
Jensen, Michael Schou
Tingskov, Stine Julie
Olinga, Peter
Nørregaard, Rikke
Mutsaers, Henricus A. M.
Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis
title Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis
title_full Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis
title_fullStr Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis
title_full_unstemmed Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis
title_short Local Inhibition of Indoleamine 2,3-Dioxygenase Mitigates Renal Fibrosis
title_sort local inhibition of indoleamine 2,3-dioxygenase mitigates renal fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389588/
https://www.ncbi.nlm.nih.gov/pubmed/34440060
http://dx.doi.org/10.3390/biomedicines9080856
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