Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease

Petra, Eleni; Siwy, Justyna; Vlahou, Antonia; Jankowski, Joachim

doi:10.1371/journal.pone.0262667

Cited by 14 publications

(8 citation statements)

References 64 publications

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“…Consistent with previous findings, we identified genes known to have a significant role in the pathogenesis of ADPKD including WNT7A, LCN2, and MMP7 (Additional files 4 and 5 ; Data files “deseq2_outputs”) (Li et al 2018 ; Petra et al 2022 ; Viau et al 2010 ; Wilk et al 2023 ; Zhou et al 2017 ). The previously noted biomarkers of CKD progression LCN2 and MMP7 were upregulated in both P28 and P21 cystic data sets (Petra et al 2022 ; Viau et al 2010 ; Zhou et al 2017 ). In line with other studies, most of the upregulated pathways in the cystic data sets P21 and P28 were associated with inflammation, leukocyte activity, NAD + activity, and cytokine response.…”

Section: Discussionsupporting

confidence: 88%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Wilk

Howton

Fisher

et al. 2023

Mol Med

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Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. Methods As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. Results With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo. Conclusion Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD. Graphical Abstract

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Section: Discussionsupporting

confidence: 88%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Wilk

Howton

Fisher

et al. 2023

Mol Med

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“…Consistent with previous findings, we identified genes known to have a significant role in the pathogenesis of ADPKD including WNT7A, LCN2, and MMP7 (Data files "deseq2_outputs"). (35,40,(68)(69)(70) The previously noted biomarkers of CKD progression LCN2 and MMP7 were upregulated in both P28 and P21 cystic data sets. (68-70) Additionally, we also found that Wnt7a, previously characterized for its role in WNT signaling in Pkd2-/-cells, was upregulated in both cystic datasets (P28 and P21).…”

Section: Discussionmentioning

confidence: 86%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion

Wilk

Howton

Fisher

et al. 2022

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) isone of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. With this approach, we prioritized 29 unique drug targets differentially expressed in ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine. Collectively, these indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

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“…Differentially expressed genes (upregulated by TGF-β but downregulated in KO5 MMC), such as Xylt1 (Tziastoudi et al, 2020), Pcsk5 (Petra et al, 2022), and Ap1s2 (Woroniecka et al, 2011;Zhong et al, 2013;Gong et al, 2016), also showed similar patterns in ATAC and H3K27ac (Supplementary Figure S7). Nlrx1 (related to mitochondrial immunity and inflammation) (Moore et al, 2008;Tattoli et al, 2008;Arnoult et al, 2009;Nagai-Singer et al, 2019) showed significantly lower expression and ATAC-peaks in KO5 MMC (Supplementary Figure S8).…”

Section: Frontiers In Molecular Biosciencesmentioning

confidence: 81%

Long non-coding RNA lncMGC mediates the expression of TGF-β-induced genes in renal cells via nucleosome remodelers

Kato

Chen

Das

et al. 2023

Front. Mol. Biosci.

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Background: MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play key roles in diabetic kidney disease (DKD). The miR-379 megacluster of miRNAs and its host transcript lnc-megacluster (lncMGC) are regulated by transforming growth factor-β (TGF-β), increased in the glomeruli of diabetic mice, and promote features of early DKD. However, biochemical functions of lncMGC are unknown. Here, we identified lncMGC-interacting proteins by in vitro-transcribed lncMGC RNA pull down followed by mass spectrometry. We also created lncMGC-knockout (KO) mice by CRISPR-Cas9 editing and used primary mouse mesangial cells (MMCs) from the KO mice to examine the effects of lncMGC on the gene expression related to DKD, changes in promoter histone modifications, and chromatin remodeling.Methods:In vitro-transcribed lncMGC RNA was mixed with lysates from HK2 cells (human kidney cell line). lncMGC-interacting proteins were identified by mass spectrometry. Candidate proteins were confirmed by RNA immunoprecipitation followed by qPCR. Cas9 and guide RNAs were injected into mouse eggs to create lncMGC-KO mice. Wild-type (WT) and lncMGC-KO MMCs were treated with TGF-β, and RNA expression (by RNA-seq and qPCR) and histone modifications (by chromatin immunoprecipitation) and chromatin remodeling/open chromatin (by Assay for Transposase-Accessible Chromatin using sequencing, ATAC-seq) were examined.Results: Several nucleosome remodeling factors including SMARCA5 and SMARCC2 were identified as lncMGC-interacting proteins by mass spectrometry, and confirmed by RNA immunoprecipitation–qPCR. MMCs from lncMGC-KO mice showed no basal or TGF-β-induced expression of lncMGC. Enrichment of histone H3K27 acetylation and SMARCA5 at the lncMGC promoter was increased in TGF-β-treated WT MMCs but significantly reduced in lncMGC-KO MMCs. ATAC peaks at the lncMGC promoter region and many other DKD-related loci including Col4a3 and Col4a4 were significantly lower in lncMGC-KO MMCs compared to WT MMCs in the TGF-β-treated condition. Zinc finger (ZF), ARID, and SMAD motifs were enriched in ATAC peaks. ZF and ARID sites were also found in the lncMGC gene.Conclusion: lncMGC RNA interacts with several nucleosome remodeling factors to promote chromatin relaxation and enhance the expression of lncMGC itself and other genes including pro-fibrotic genes. The lncMGC/nucleosome remodeler complex promotes site-specific chromatin accessibility to enhance DKD-related genes in target kidney cells.

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Urine peptidome in combination with transcriptomics analysis highlights MMP7, MMP14 and PCSK5 for further investigation in chronic kidney disease

Cited by 14 publications

References 64 publications

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion

Long non-coding RNA lncMGC mediates the expression of TGF-β-induced genes in renal cells via nucleosome remodelers

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