Evidence for activation of the unfolded protein response in collagen IV nephropathies

Thin-basement-membrane nephropathy (TBMN) and Alport syndrome (AS) are progressive collagen IV nephropathies caused by mutations in COL4A3/A4/A5 genes. These nephropathies invariably present with microscopic hematuria and frequently progress to proteinuria and CKD or ESRD during long-term follow-up....

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Published in:Journal of the American Society of Nephrology Vol. 25; no. 2; p. 260
Main Authors: Pieri, Myrtani, Stefanou, Charalambos, Zaravinos, Apostolos, Erguler, Kamil, Stylianou, Kostas, Lapathitis, George, Karaiskos, Christos, Savva, Isavella, Paraskeva, Revekka, Dweep, Harsh, Sticht, Carsten, Anastasiadou, Natassa, Zouvani, Ioanna, Goumenos, Demetris, Felekkis, Kyriakos, Saleem, Moin, Voskarides, Konstantinos, Gretz, Norbert, Deltas, Constantinos
Format: Journal Article
Language:English
Published: United States 01.02.2014
Subjects:
Animals
Autoantigens - genetics
Autoantigens - physiology
Biopsy
Cells, Cultured
Collagen Type IV - deficiency
Collagen Type IV - genetics
Collagen Type IV - physiology
Disease Models, Animal
DNA-Binding Proteins - metabolism
Endoplasmic Reticulum Stress - physiology
Gene Expression Profiling
Gene Knock-In Techniques
Glomerular Basement Membrane - metabolism
Glomerular Basement Membrane - pathology
Heat-Shock Proteins - biosynthesis
Heat-Shock Proteins - genetics
Heterozygote
Humans
Kidney - metabolism
Kidney - pathology
Mice
Mutation, Missense
Nephritis, Hereditary - genetics
Nephritis, Hereditary - metabolism
Nephritis, Hereditary - pathology
Oligonucleotide Array Sequence Analysis
Podocytes - metabolism
Podocytes - pathology
Point Mutation
Protein Array Analysis
Protein Transport
Recombinant Fusion Proteins
Regulatory Factor X Transcription Factors
RNA Interference
RNA, Small Interfering - pharmacology
Transcription Factors - metabolism
Transfection
Unfolded Protein Response - physiology
ISSN:1533-3450, 1533-3450
Online Access:Get more information
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Summary:Thin-basement-membrane nephropathy (TBMN) and Alport syndrome (AS) are progressive collagen IV nephropathies caused by mutations in COL4A3/A4/A5 genes. These nephropathies invariably present with microscopic hematuria and frequently progress to proteinuria and CKD or ESRD during long-term follow-up. Nonetheless, the exact molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus remain elusive. We hypothesized that defective trafficking of the COL4A3 chain causes a strong intracellular effect on the cell responsible for COL4A3 expression, the podocyte. To this end, we overexpressed normal and mutant COL4A3 chains (G1334E mutation) in human undifferentiated podocytes and tested their effects in various intracellular pathways using a microarray approach. COL4A3 overexpression in the podocyte caused chain retention in the endoplasmic reticulum (ER) that was associated with activation of unfolded protein response (UPR)-related markers of ER stress. Notably, the overexpression of normal or mutant COL4A3 chains differentially activated the UPR pathway. Similar results were observed in a novel knockin mouse carrying the Col4a3-G1332E mutation, which produced a phenotype consistent with AS, and in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation. These results suggest that ER stress arising from defective localization of collagen IV chains in human podocytes contributes to the pathogenesis of TBMN and AS through activation of the UPR, a finding that may pave the way for novel therapeutic interventions for a variety of collagenopathies.
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ISSN:1533-3450
1533-3450
DOI:10.1681/ASN.2012121217