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A human integrin-α3 mutation confers major renal developmental defects.

ABSTRACT: Integrin-α3 plays a central role in the interplay of cells, morphogens and ECM, required for proper nephrogenesis, thus adding ITGA3 to the list of CAKUT (congenital anomalies of the kidney and urinary tract)-causing genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54227 | GEO | 2014/12/15

SECONDARY ACCESSION(S): PRJNA236572

REPOSITORIES: GEO

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A human integrin-?3 mutation confers major renal developmental defects.

Project description:Integrin-?3 plays a central role in the interplay of cells, morphogens and ECM, required for proper nephrogenesis, thus adding ITGA3 to the list of CAKUT (congenital anomalies of the kidney and urinary tract)-causing genes. we used renal tissue originally obtained from a patient with an ITGA3 mutation and assessed its gene expression profile as compared to controls

2014-12-15 | E-GEOD-54227 | biostudies-arrayexpress

Absence of integrin α3 modulates the integrin landscape of human keratinocytes

Project description:Integrins are among the most abundant cell surface receptors constituting the principal adhesion receptors for the extracellular matrix (ECM), providing a physical anchor for the cell and triggering multiple intracellular signalling events. Loss-of function mutations of the integrin α3 gene (ITGA3) have been recently disclosed in patients with interstitial lung disease, congenital nephrotic syndrome and junctional epidermolysis bullosa, a multiorgan disorder with fatal outcome. In these patients, the respiratory function is strongly impaired and the kidneys are variably affected, whereas skin fragility is rather mild, has a delayed onset after birth or remains unrecognized, suggesting that integrin α3 differently influences the development and homeostasis of these organs. Here we employed authentic human keratinocytes bearing a naturally occurring integrin α3 loss-of-function mutation as a prototype to characterize the molecular mechanisms launched by the constitutional absence of this integrin subunit. To validate our findings, we generated new cellular models, including an additional ILNEB patient cell line, ITGA3 rescued and knockdown cells. We show that keratinocytes lacking a functional α3 subunit have an activated cellular phenotype with a switch in the pattern of integrin α subunits on the cell surface. These assure spreading and adhesion of epidermal keratinocytes but also drive the migratory phenotype of these cells.

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Integrated analysis of copy number variation-associated lncRNAs identifies candidates contributing to the etiologies of congenital kidney anomalies.

Project description:We analyzed lncRNAs located in CNV loci associated with congenital anomalies of the kidney and urinary tract (CAKUT). HSALNG0134318 at CNV 22q11 was identified as CAKUT related lncRNA, which was coexpressed with multiple known CAKUT associated genes. To validate our findings, we performed knockdown experiments in HEK293 cell line to characterize the trascriptomic profiles regulated by HSALNG0134318 in human embryonic kidney cells.

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Integrin α3-dependent gene expression in Th17 cells generated during experimental autoimmune encephalomyelitis

Project description:To understand the global gene expression changes in Itga3-deficient Th17 cells, we performed RNA-seq with fate-mapped Th17 cells isolated from inguinal lymph nodes of EAE-induced mice at day 7 post EAE induction.

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Nano-LC-MS/MS proteomics in amniotic fluid from CAKUT patients

Project description:The objective of the present work was to identify new renal proteins responsible for Congenital Anomalies of the Kidney and of the Urinary Tract (CAKUT pathophysiology). We conducted a comparative LC-MS/MS-based proteomics analysis of amniotic fluids (AF) collected from non-severe CAKUT (ns-CAKUT; n=19), severe CAKUT (s-CAKUT; n=14), and healthy controls (cont; n=22) fetuses. We identified a total of 224 gestational age independent proteins that were significantly different in abundance when comparing (one-way ANOVA corrected p<0.05) the 3 groups of amniotic fluids 2 by 2. We identified 8 gestational-age independent proteins that were in common when comparing the 3 groups two by two, and that were considered as associated to both CAKUT onset and CAKUT severity.

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N6-Methyladenosine Methylomic Landscape of Ureteral Deficiency in Reflux Uropathy and Obstructive Uropathy

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Project description:Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of lung or kidney fibrosis. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and treat lung fibrosis and inhibit kidney fibrosis in vivo. Decorin’s collagen-binding peptide can be used to direct functionalized blocking antibodies (against integrins-α3, -αM, -αMβ2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to treat fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment of fibrosis.

2024-09-25 | GSE273713 | GEO

Overexpression of long noncoding RNA 4933425B07Rik leads to renal hypoplasia by inactivating the Wnt/β-catenin signaling pathway

Project description:Background Congenital anomalies of the kidney and urinary tract (CAKUT) refer to a diverse group of developmental malformations, which are the leading cause of chronic kidney disease and end-stage renal disease in children. The etiology and pathogenesis of CAKUT are complex. In recent years, the relationship between long noncoding RNAs and renal development and disease has attracted much attention. Our previous study established a long noncoding RNA 4933425B07Rik (Rik) overexpression mouse model by inserting the PB transposon and found that overexpression of Rik led to renal hypoplasia. This study aimed to explore the molecular mechanism of renal hypoplasia induced by Rik overexpression in vitro. Results In this study, by constructing Rik overexpression cell models and a Rik knockout cell model to accompany previously developed RikPB/PB;Hoxb7 mice and by applying RNA-seq, RT‒PCR and other experimental methods, it was found that when Rik was highly expressed, the expression of Wnt10b, Fzd8 and β-catenin decreased, while Rik was knock down, the expression of these genes increased. Conclusions The findings suggest that overexpression of Rik leads to renal hypoplasia by inactivating the Wnt/β-catenin signaling pathway. This research perspective may provide a basis for exploring new causes and mechanisms of CAKUT and provide new targets for the prevention and treatment of CAKUT.

2022-08-30 | GSE212130 | GEO

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Project description:Gene-level and exon-level analysis of gene expression in MDA-MB-231 cells that stably express control shRNA or integrin α3-targeting shRNA. The laminin-332-binding integrin α3b1 is expressed highly in many breast cancer cells, but its roles in regulating gene expression programs that promote breast cancer progression have not been explored. In order to identify genes that are regulated by α3b1 in human breast cancer cells, we used a lentiviral approach to express an α3-targeting shRNA to suppress integrin α3b1 in MDA-MB-231 cells, and we identified subsequent changes in gene expression and alternate exon useage. We used the Affymetrix Human Exon 1.0 ST platform to analyze biological replicates of MDA-MB-231 cells that were transduced with lentivirus to stably express either control shRNA or α3-targeting shRNA. Array data was processed by Affymetrix Exon Array Computational Tool.

2014-05-02 | E-GEOD-43097 | biostudies-arrayexpress

DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2

Project description:Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney caused causes ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20 and polycystin-2 (PC2) were are reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was is recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

2024-05-14 | PXD051912 | Pride

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