Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease
Abstract CYP3A5 is the primary CYP3A subfamily enzyme expressed in the human kidney and its aberrant expression may contribute to a broad spectrum of renal disorders. Pharmacogenetic studies have reported inconsistent linkages between CYP3A5 expression and hypertension, however, most investigators h...
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2021
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oai:doaj.org-article:a3c201a0a7084bb899171d4e7331ae732021-12-02T13:20:22ZAntisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease10.1038/s41598-021-84194-w2045-2322https://doaj.org/article/a3c201a0a7084bb899171d4e7331ae732021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84194-whttps://doaj.org/toc/2045-2322Abstract CYP3A5 is the primary CYP3A subfamily enzyme expressed in the human kidney and its aberrant expression may contribute to a broad spectrum of renal disorders. Pharmacogenetic studies have reported inconsistent linkages between CYP3A5 expression and hypertension, however, most investigators have considered CYP3A5*1 as active and CYP3A5*3 as an inactive allele. Observations of gender specific differences in CYP3A5*3/*3 protein expression suggest additional complexity in gene regulation that may underpin an environmentally responsive role for CYP3A5 in renal function. Reconciliation of the molecular mechanism driving conditional restoration of functional CYP3A5*3 expression from alternatively spliced transcripts, and validation of a morpholino-based approach for selectively suppressing renal CYP3A5 expression, is the focus of this work. Morpholinos targeting a cryptic splice acceptor created by the CYP3A5*3 mutation in intron 3 rescued functional CYP3A5 expression in vitro, and salt-sensitive cellular mechanisms regulating splicing and conditional expression of CYP3A5*3 transcripts are reported. The potential for a G-quadruplex (G4) in intron 3 to mediate restored splicing to exon 4 in CYP3A5*3 transcripts was also investigated. Finally, a proximal tubule microphysiological system (PT-MPS) was used to evaluate the safety profile of morpholinos in proximal tubule epithelial cells, highlighting their potential as a therapeutic platform for the treatment of renal disease.Kevin A. LidbergAndrew J. AnnaloraMarija JozicDaniel J. ElsonLu WangTheo K. BammlerSusanne RammMaria Beatriz MonteiroJonathan HimmelfarbCraig B. MarcusPatrick L. IversenEdward J. KellyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021) |
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Medicine R Science Q Kevin A. Lidberg Andrew J. Annalora Marija Jozic Daniel J. Elson Lu Wang Theo K. Bammler Susanne Ramm Maria Beatriz Monteiro Jonathan Himmelfarb Craig B. Marcus Patrick L. Iversen Edward J. Kelly Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease |
description |
Abstract CYP3A5 is the primary CYP3A subfamily enzyme expressed in the human kidney and its aberrant expression may contribute to a broad spectrum of renal disorders. Pharmacogenetic studies have reported inconsistent linkages between CYP3A5 expression and hypertension, however, most investigators have considered CYP3A5*1 as active and CYP3A5*3 as an inactive allele. Observations of gender specific differences in CYP3A5*3/*3 protein expression suggest additional complexity in gene regulation that may underpin an environmentally responsive role for CYP3A5 in renal function. Reconciliation of the molecular mechanism driving conditional restoration of functional CYP3A5*3 expression from alternatively spliced transcripts, and validation of a morpholino-based approach for selectively suppressing renal CYP3A5 expression, is the focus of this work. Morpholinos targeting a cryptic splice acceptor created by the CYP3A5*3 mutation in intron 3 rescued functional CYP3A5 expression in vitro, and salt-sensitive cellular mechanisms regulating splicing and conditional expression of CYP3A5*3 transcripts are reported. The potential for a G-quadruplex (G4) in intron 3 to mediate restored splicing to exon 4 in CYP3A5*3 transcripts was also investigated. Finally, a proximal tubule microphysiological system (PT-MPS) was used to evaluate the safety profile of morpholinos in proximal tubule epithelial cells, highlighting their potential as a therapeutic platform for the treatment of renal disease. |
format |
article |
author |
Kevin A. Lidberg Andrew J. Annalora Marija Jozic Daniel J. Elson Lu Wang Theo K. Bammler Susanne Ramm Maria Beatriz Monteiro Jonathan Himmelfarb Craig B. Marcus Patrick L. Iversen Edward J. Kelly |
author_facet |
Kevin A. Lidberg Andrew J. Annalora Marija Jozic Daniel J. Elson Lu Wang Theo K. Bammler Susanne Ramm Maria Beatriz Monteiro Jonathan Himmelfarb Craig B. Marcus Patrick L. Iversen Edward J. Kelly |
author_sort |
Kevin A. Lidberg |
title |
Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease |
title_short |
Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease |
title_full |
Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease |
title_fullStr |
Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease |
title_full_unstemmed |
Antisense oligonucleotide development for the selective modulation of CYP3A5 in renal disease |
title_sort |
antisense oligonucleotide development for the selective modulation of cyp3a5 in renal disease |
publisher |
Nature Portfolio |
publishDate |
2021 |
url |
https://doaj.org/article/a3c201a0a7084bb899171d4e7331ae73 |
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