Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats
MicroRNAs (miRNAs) are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of non-alcoholic fatty liver disease. Here, we investigated the phosphodiesterase 5 (PDE5) inhibitor induced effects on hepatic an...
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MDPI AG
2021-12-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/22/1/382 |
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doaj-0e17b3d923254f18b7ac57924da415f5 |
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record_format |
Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andre Broermann Ramona Schmid Ogsen Gabrielyan Marlene Sakowski Claudia Eisele Sascha Keller Michael Wolff Patrick Baum Birgit Stierstorfer Jochen Huber Bernhard K. Krämer Berthold Hocher Ruediger Streicher Denis Delić |
spellingShingle |
Andre Broermann Ramona Schmid Ogsen Gabrielyan Marlene Sakowski Claudia Eisele Sascha Keller Michael Wolff Patrick Baum Birgit Stierstorfer Jochen Huber Bernhard K. Krämer Berthold Hocher Ruediger Streicher Denis Delić Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats International Journal of Molecular Sciences liver fibrosis CCl<sub>4</sub> PDE 5 inhibitor gene expression microRNAs exosomes |
author_facet |
Andre Broermann Ramona Schmid Ogsen Gabrielyan Marlene Sakowski Claudia Eisele Sascha Keller Michael Wolff Patrick Baum Birgit Stierstorfer Jochen Huber Bernhard K. Krämer Berthold Hocher Ruediger Streicher Denis Delić |
author_sort |
Andre Broermann |
title |
Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats |
title_short |
Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats |
title_full |
Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats |
title_fullStr |
Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats |
title_full_unstemmed |
Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated Rats |
title_sort |
exosomal mirnas as potential biomarkers to monitor phosphodiesterase 5 inhibitor induced anti-fibrotic effects on ccl<sub>4</sub> treated rats |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-12-01 |
description |
MicroRNAs (miRNAs) are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of non-alcoholic fatty liver disease. Here, we investigated the phosphodiesterase 5 (PDE5) inhibitor induced effects on hepatic and plasma exosomal miRNA expression in CCl<sub>4</sub>-treated rats. In the present study, hepatic miRNA profiling was conducted using the Nanostring nCounter technology and mRNA profiling using RNA sequencing from PDE5 treated rats in the model of CCl<sub>4</sub>-induced liver fibrosis. To evaluate if the PDE5 inhibitor affected differentially expressed miRNAs in the liver can be detected in plasma exosomes, qRT-PCR specific assays were used. In livers from CCl<sub>4</sub>-treated rats, the expression of 22 miRNAs was significantly increased (> 1.5-fold, adj. <i>p </i>< 0.05), whereas the expression of 16 miRNAs was significantly decreased (> 1.5-fold, adj. <i>p</i> < 0.05). The majority of the deregulated miRNA species are implicated in fibrotic and inflammatory processes. The PDE5 inhibitor suppressed the induction of pro-fibrotic miRNAs, such as miR-99b miR-100 and miR-199a-5p, and restored levels of anti-fibrotic miR-122 and miR-192 in the liver. In plasma exosomes, we observed elevated levels of miR-99b, miR-100 and miR-142-3p after treatment with the PDE5-inhibitor compared to CCl<sub>4</sub>/Vehicle-treated. Our study demonstrated for the first time that during the development of hepatic fibrosis in the preclinical model of CCl<sub>4</sub>-induced liver fibrosis, defined aspects of miRNA regulated liver pathogenesis are influenced by PDE5 treatment. In conclusion, miRNA profiling of plasma exosomes might be used as a biomarker for NASH progression and monitoring of treatment effects. |
topic |
liver fibrosis CCl<sub>4</sub> PDE 5 inhibitor gene expression microRNAs exosomes |
url |
https://www.mdpi.com/1422-0067/22/1/382 |
work_keys_str_mv |
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doaj-0e17b3d923254f18b7ac57924da415f52021-01-01T00:06:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-012238238210.3390/ijms22010382Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl<sub>4</sub> Treated RatsAndre Broermann0Ramona Schmid1Ogsen Gabrielyan2Marlene Sakowski3Claudia Eisele4Sascha Keller5Michael Wolff6Patrick Baum7Birgit Stierstorfer8Jochen Huber9Bernhard K. Krämer10Berthold Hocher11Ruediger Streicher12Denis Delić13Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyDrug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyDrug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyClinical Operations, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, 68167 Mannheim, GermanyFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, 68167 Mannheim, GermanyCardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, GermanyMicroRNAs (miRNAs) are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of non-alcoholic fatty liver disease. Here, we investigated the phosphodiesterase 5 (PDE5) inhibitor induced effects on hepatic and plasma exosomal miRNA expression in CCl<sub>4</sub>-treated rats. In the present study, hepatic miRNA profiling was conducted using the Nanostring nCounter technology and mRNA profiling using RNA sequencing from PDE5 treated rats in the model of CCl<sub>4</sub>-induced liver fibrosis. To evaluate if the PDE5 inhibitor affected differentially expressed miRNAs in the liver can be detected in plasma exosomes, qRT-PCR specific assays were used. In livers from CCl<sub>4</sub>-treated rats, the expression of 22 miRNAs was significantly increased (> 1.5-fold, adj. <i>p </i>< 0.05), whereas the expression of 16 miRNAs was significantly decreased (> 1.5-fold, adj. <i>p</i> < 0.05). The majority of the deregulated miRNA species are implicated in fibrotic and inflammatory processes. The PDE5 inhibitor suppressed the induction of pro-fibrotic miRNAs, such as miR-99b miR-100 and miR-199a-5p, and restored levels of anti-fibrotic miR-122 and miR-192 in the liver. In plasma exosomes, we observed elevated levels of miR-99b, miR-100 and miR-142-3p after treatment with the PDE5-inhibitor compared to CCl<sub>4</sub>/Vehicle-treated. Our study demonstrated for the first time that during the development of hepatic fibrosis in the preclinical model of CCl<sub>4</sub>-induced liver fibrosis, defined aspects of miRNA regulated liver pathogenesis are influenced by PDE5 treatment. In conclusion, miRNA profiling of plasma exosomes might be used as a biomarker for NASH progression and monitoring of treatment effects.https://www.mdpi.com/1422-0067/22/1/382liver fibrosisCCl<sub>4</sub>PDE 5 inhibitorgene expressionmicroRNAsexosomes |