Comparative transcriptomics of shear stress treated Pkd1−/− cells and pre-cystic kidneys reveals pathways involved in early polycystic kidney disease

Kunnen, Steven J.; Malas, Tareq B.; Formica, Chiara; Leonhard, Wouter N.; Hoen, Peter A.C. ‘t; Peters, Dorien J.M.

doi:10.1016/j.biopha.2018.07.178

Cited by 20 publications

(25 citation statements)

References 87 publications

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“…Importantly, FSS did not enhance the ATP release in Pkd1 −/− cells, corroborating the lack of mechanosensitive ATP extrusion in these cells. Dysfunctional PC1 also critically affects the transcriptome of kidney cells . In addition, increased expression of pannexin‐1 in cyst lining cells of a mouse and rat PKD model has recently been reported .…”

Section: Discussionmentioning

confidence: 99%

Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease

et al. 2020

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are contributed equally to this work.Abbreviations: Abcc6, ATP binding cassette subfamily c member 6; BB-FCF, brilliant blue-FCF; Cx30, connexin30; Cx30.3, connexin30.3; Cx37, connexin37; Entpd2, ectonucleoside triphosphate diphosphohydrolase 2; Entpd3, ectonucleoside triphosphate diphosphohydrolase 3; FBS, fetal bovine serum; FSS, fluid shear stress; Gapdh, glyceraldehyde 3-phosphate dehydrogenase; MO, translation blocking morpholino; Nt5e, ecto-5′-nucleotidase; Panx1, pannexin-1; PC1, polycystin-1; PC2, polycystin-2; PKD, polycystic kidney disease; Pkd1, polycystic kidney disease 1; Pkd2, polycystic kidney disease 2; Ptgs2, prostaglandin-endoperoxide synthase 2. AbstractTubular ATP release is regulated by mechanosensation of fluid shear stress (FSS).Polycystin-1/polycystin-2 (PC1/PC2) functions as a mechanosensory complex in the kidney. Extracellular ATP is implicated in polycystic kidney disease (PKD), where PC1/PC2 is dysfunctional. This study aims to provide new insights into the ATP signaling under physiological conditions and PKD. Microfluidics, pharmacologic inhibition, and loss-of-function approaches were combined to assess the ATP release in mouse distal convoluted tubule 15 (mDCT15) cells. Kidney-specific Pkd1 knockout mice (iKsp-Pkd1 −/− ) and zebrafish pkd2 morphants (pkd2-MO) were as models for PKD. FSS-exposed mDCT15 cells displayed increased ATP release. Pannexin-1 inhibition and knockout decreased FSS-modulated ATP release. In iKsp-Pkd1 −/− mice, elevated renal pannexin-1 mRNA expression and urinary ATP were observed. In Pkd1 −/− mDCT15 cells, elevated ATP release was observed upon the FSS mechanosensation. In these cells, increased pannexin-1 mRNA expression was observed.Importantly, pannexin-1 inhibition in pkd2-MO decreased the renal cyst growth. Our results demonstrate that pannexin-1 channels mediate ATP release into the tubular lumen due to pro-urinary flow. We present pannexin-1 as novel therapeutic target to prevent the renal cyst growth in PKD. K E Y W O R D SATP, fluid shear stress, pannexin-1, polycystin-1, purinergic signaling | 6383 VERSCHUREN Et al.

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Section: Discussionmentioning

confidence: 99%

Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease

et al. 2020

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“…These observations imply the involvement of the Hippo pathway in MVID. Second, the Hippo pathway is required for proper development of kidneys, and its deficiency is relevant to various kidney diseases including polycystic kidney disease (PKD), in which epithelial cysts replace normal renal tubes (Happé et al 2011;Reginensi et al 2013;Seo et al 2016;Jiang et al 2017;Kunnen et al 2018;Xu et al 2018). Patients with autosomal dominant (AD) PKD show defective membrane polarity, mislocalization of apical proteins to the basolateral domain, and mislocalization of normally basolateral proteins to the apical, luminal membrane (Wilson et al 1991;Du and Wilson 1995;Lebeau et al 2002).…”

Section: Discussionmentioning

confidence: 99%

The Hippo Pathway Is Essential for Maintenance of Apicobasal Polarity in the Growing Intestine of Caenorhabditis elegans

Lee¹,

Kang

Ahn³

et al. 2019

Genetics

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Although multiple determinants for establishing polarity in membranes of epithelial cells have been identified, the mechanism for maintaining apicobasal polarity is not fully understood. Here, we show that the conserved Hippo kinase pathway plays a role in the maintenance of apicobasal polarity in the developing intestine of Caenorhabditis elegans. We screened suppressors of the mutation in wts-1-the gene that encodes the LATS kinase homolog, deficiency of which leads to disturbance of the apicobasal polarity of the intestinal cells and to eventual death of the organism. We identified several alleles of yap-1 and egl-44 that suppress the effects of this mutation. yap-1 encodes a homolog of YAP/Yki, and egl-44 encodes a homolog of TEAD/Sd. WTS-1 bound directly to YAP-1 and inhibited its nuclear accumulation in intestinal cells. We also found that NFM-1, which is a homolog of NF2/Merlin, functioned in the same genetic pathway as WTS-1 to regulate YAP-1 to maintain cellular polarity. Transcriptome analysis identified several target candidates of the YAP-1-EGL-44 complex including TAT-2, which encodes a putative P-type ATPase. In summary, we have delineated the conserved Hippo pathway in C. elegans consisting of NFM-1-WTS-1-YAP-1-EGL-44 and proved that the proper regulation of YAP-1 by upstream NFM-1 and WTS-1 is essential for maintenance of apicobasal membrane identities of the growing intestine.

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“…To our knowledge, no study has focused on the correlation between ADPKD and the ADM/IER3 genes. However, MYC/ADM/IER3 frequently appear in the lists of upregulated DEGs identified via transcriptomic analyses in various ADPKD-related studies [25,26,[49][50][51][52][53]. In addition, adrenomedullin, encoded by ADM, is a potent hypotensive peptide and has been associated with hypertension and chronic kidney disease (CKD) [54,55].…”

Section: Resultsmentioning

confidence: 99%

“…Identification of the differentially expressed gene (DEG) set (adjusted p-value ≤ 0.05 and |log 2 Fold Change| ≥ 0.26) was then performed with the DESeq2 (version 1.26.0) package [24]. In addition, a threshold counts per million (CPM) value was set to exclude hits with low expression levels (CPM < 2) [25,26]. The expression data were submitted to the Gene Expression Omnibus with the following accession number: GSE141355.…”

Section: Rna-seqmentioning

confidence: 99%

Identification of ADPKD-Related Genes and Pathways in Cells Overexpressing PKD2

Zhang

Dang

Wang

et al. 2020

Genes

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Consistent with the gene dosage effect hypothesis, renal cysts can arise in transgenic murine models overexpressing either PKD1 or PKD2, which are causal genes for autosomal dominant polycystic kidney disease (ADPKD). To determine whether PKD gene overexpression is a universal mechanism driving cystogenesis or is merely restricted to rodents, other animal models are required. Previously, we failed to observe any renal cysts in a transgenic porcine model of PKD2 overexpression partially due to epigenetic silencing of the transgene. Thus, to explore the feasibility of porcine models and identify potential genes/pathways affected in ADPKD, LLC-PK1 cells with high PKD2 expression were generated. mRNA sequencing (RNA-seq) was performed, and MYC, IER3, and ADM were found to be upregulated genes common to the different PKD2 overexpression cell models. MYC is a well-characterized factor contributing to cystogenesis, and ADM is a biomarker for chronic kidney disease. Thus, these genes might be indicators of disease progression. Additionally, some ADPKD-associated pathways, e.g., the mitogen-activated protein kinase (MAPK) pathway, were enriched in the cells. Moreover, gene ontology (GO) analysis demonstrated that proliferation, apoptosis, and cell cycle regulation, which are hallmarks of ADPKD, were altered. Therefore, our experiment identified some biomarkers or indicators of ADPKD, indicating that high PKD2 expression would likely drive cystogenesis in future porcine models.

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Comparative transcriptomics of shear stress treated Pkd1−/− cells and pre-cystic kidneys reveals pathways involved in early polycystic kidney disease

Cited by 20 publications

References 87 publications

Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease

Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease

The Hippo Pathway Is Essential for Maintenance of Apicobasal Polarity in the Growing Intestine of Caenorhabditis elegans

Identification of ADPKD-Related Genes and Pathways in Cells Overexpressing PKD2

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