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JAK inhibitors dampen activation of interferon-activated transcriptomes and the SARS-CoV-2 receptor ACE2 in human renal proximal tubules.

ABSTRACT: SARS-CoV-2 infections initiate cytokine storms and activate genetic programs leading to progressive hyperinflammation in multiple organs of patients with COVID-19. While it is known that COVID-19 impacts kidney function, leading to increased mortality, cytokine response of renal epithelium has not been studied in detail. Here, we report on the genetic programs activated in human primary proximal tubule (HPPT) cells by interferons and their suppression by ruxolitinib, a Janus kinase (JAK) inhibitor used in COVID-19 treatment. Integration of our data with those from patients with acute kidney injury and COVID-19, as well as other tissues, permitted the identification of kidney-specific interferon responses. Additionally, we investigated the regulation of the recently discovered isoform (dACE2) of the angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. Using ChIP-seq, we identified candidate interferon-activated enhancers controlling the ACE2 locus, including the intronic dACE2 promoter. Taken together, our study provides an in-depth understanding of genetic programs activated in kidney cells.

SUBMITTER: Jankowski J

PROVIDER: S-EPMC8321697 | biostudies-literature |

REPOSITORIES: biostudies-literature

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JAK inhibitors dampen activation of interferon-activated transcriptomes and the SARS-CoV-2 receptor ACE2 in human renal proximal tubules

Project description:SARS-CoV-2 infections initiate cytokine storms and activate genetic programs leading to progressive hyperinflammation in multiple organs of patients with COVID-19. While it is known that COVID-19 impacts kidney function, leading to increased mortality, cytokine response of renal epithelium has not been studied in detail. Here, we report on the genetic programs activated in human primary proximal tubule (HPPT) cells by interferons and their suppression by ruxolitinib, a Janus kinase (JAK) inhibitor used in COVID-19 treatment. Integration of our data with those from patients with acute kidney injury and COVID-19, as well as other tissues, permitted the identification of kidney-specific interferon responses. Additionally, we investigated the regulation of the recently discovered isoform (dACE2) of the angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. Using ChIP-seq, we identified candidate interferon-activated enhancers controlling the ACE2 locus, including the intronic dACE2 promoter. Taken together, our study provides an in-depth understanding of genetic programs activated in kidney cells.

2021-02-03 | GSE161917 | GEO

JAK inhibitors dampen activation of interferon-activated transcriptomes and the SARS-CoV-2 receptor ACE2 in human renal proximal tubules

Project description:JAK inhibitors dampen activation of interferon-activated transcriptomes and the SARS-CoV-2 receptor ACE2 in human renal proximal tubules

| PRJNA679822 | ENA

Interferon-regulated genetic programs and JAK/STAT pathway activate the intronic promoter of the short ACE2 isoform in renal proximal tubules.

Project description:Recently, a short, interferon-inducible isoform of Angiotensin-Converting Enzyme 2 (ACE2), dACE2 was identified. ACE2 is a SARS-Cov-2 receptor and changes in its renal expression have been linked to several human nephropathies. These changes were never analyzed in context of dACE2 , as its expression was not investigated in the kidney. We used Human Primary Proximal Tubule (HPPT) cells to show genome-wide gene expression patterns after cytokine stimulation, with emphasis on the ACE2/dACE2 locus. Putative regulatory elements controlling dACE2 expression were identified using ChIP-seq and RNA-seq. qRT-PCR differentiating between ACE2 and dACE2 revealed 300- and 600-fold upregulation of dACE2 by IFN? and IFN?, respectively, while full length ACE2 expression was almost unchanged. JAK inhibitor ruxolitinib ablated STAT1 and dACE2 expression after interferon treatment. Finally, with RNA-seq, we identified a set of genes, largely immune-related, induced by cytokine treatment. These gene expression profiles provide new insights into cytokine response of proximal tubule cells.

| S-EPMC7836111 | biostudies-literature

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells.

Project description:SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

| S-EPMC8172581 | biostudies-literature

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells

2021-04-23 | GSE161665 | GEO

Interferon-regulated genetic programs and JAK/STAT pathway activate the intronic promoter of the short ACE2 isoform in renal proximal tubules [ChIP-seq]

Project description:Angiotensin-Converting Enzyme 2 (ACE2) binds SARS-CoV-2 spike protein and facilitates viral entry into the cell. ACE2 is expressed in the kidney and renal injury strongly impacts COVID-19 prognosis. In addition, a short, interferon-inducible isoform of ACE2, dACE2 was recently identified. Change in ACE2 expression has already been linked to several human nephropathies. However, these changes were not analyzed in context of dACE2 and regulation of ACE2 expression in the kidney remains unclear. Human primary Renal Proximal Tubule cells were used for all experiments. ChIP-seq analysis of histone modifications (H3K27ac, H3K4me3, K3K4me1), RNA polymerase loading and DNAse hypersensitive sites (DHS) were used to identify gene regulatory elements in the ACE2 locus. qRT-PCR was used to assess mRNA expression of ACE2, dACE2, TMPRSS2 and STAT1. RNA-seq was used to identify changes in global gene expression after cytokine treatment. Putative regulatory elements controlling dACE2 expression were identified using ChIP-seq profiles and RNA-seq mapping. qRT-PCR differentiating between ACE2 and dACE2 revealed that only dACE2 is interferon inducible. dACE2 mRNA was upregulated 300- and 600-fold by IFNα and IFNβ, respectively, while full length ACE2 was unchanged. Interferon stimulation also resulted in elevated STAT1 expression. JAK inhibitor ruxolitinib ablated both STAT1 and dACE2 expression after interferon treatment. RNA-seq analysis revealed approximately 1200 genes induced by IFNβ, largely innate immune response-related. We showed that human primary proximal tubules express ACE2 and its interferon-inducible short isoform, dACE2, from an intronic promoter. We also deliver new datasets identifying cytokine response genes in proximal tubule cells.

2021-02-03 | GSE161915 | GEO

Interferon-regulated genetic programs and JAK/STAT pathway activate the intronic promoter of the short ACE2 isoform in renal proximal tubules [RNA-seq]

2021-02-03 | GSE161916 | GEO

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (RNA-seq)

Project description:SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

2021-04-23 | GSE161664 | GEO

JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (ChIP-seq)

Project description:SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.

2021-04-23 | GSE161663 | GEO

Bioprinting of 3D Convoluted Renal Proximal Tubules on Perfusable Chips.

Project description:Three-dimensional models of kidney tissue that recapitulate human responses are needed for drug screening, disease modeling, and, ultimately, kidney organ engineering. Here, we report a bioprinting method for creating 3D human renal proximal tubules in vitro that are fully embedded within an extracellular matrix and housed in perfusable tissue chips, allowing them to be maintained for greater than two months. Their convoluted tubular architecture is circumscribed by proximal tubule epithelial cells and actively perfused through the open lumen. These engineered 3D proximal tubules on chip exhibit significantly enhanced epithelial morphology and functional properties relative to the same cells grown on 2D controls with or without perfusion. Upon introducing the nephrotoxin, Cyclosporine A, the epithelial barrier is disrupted in a dose-dependent manner. Our bioprinting method provides a new route for programmably fabricating advanced human kidney tissue models on demand.

| S-EPMC5057112 | biostudies-literature

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