Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice

Beirowski, Bogdan; Weber, Manfred; Groß, Oliver

doi:10.1681/asn.2005101044

Cited by 43 publications

(41 citation statements)

References 42 publications

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“…This is also supported by similar findings in a COL4A3ϩ/Ϫ knockout murine model that develops TBMN coinciding with focal glomerulosclerosis and other renal pathology. 45 In addition, the presence of phenotypic heterogeneity allows the hypothesis that genetic modifiers and/or a co-inherited glomerulopathy may contribute to the disease course. One way to deal with the significant variable expressivity in carriers of such mutations might be to refer to them collectively as COL4A3/ COL4A4 nephropathies, thereby treating them under a unifying molecular terminology.…”

Section: Mutation Screening Dna Sequencing and Founder Effectsmentioning

confidence: 99%

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Voskarides¹,

Damianou²,

Neocleous³

et al. 2007

Journal of the American Society of Nephrology

189

178

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Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in ϳ40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.

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Section: Mutation Screening Dna Sequencing and Founder Effectsmentioning

confidence: 99%

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Voskarides¹,

Damianou²,

Neocleous³

et al. 2007

Journal of the American Society of Nephrology

189

178

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“…The cause of the renal impairment in the latter group of patients is unknown. Heterozygotes in a COL4A3 knockout have been proposed as a model for TBMD [40]. This model shows focal glomerulosclerosis, tubulointerstitial fibrosis with upregulation of TGFβ and should be beneficial for exploring both pathogenesis and therapeutic options for those patients who develop progressive renal disease in TBMN.…”

Section: Molecular Pathogenesis Of Thin Basement Membrane Nephropathymentioning

confidence: 99%

Alport Syndrome and Thin Basement Membrane Nephropathy

Thorner

2007

Nephron Clin Pract

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Both Alport syndrome and thin basement membrane nephropathy (TBMN) can be considered as genetic diseases of the GBM involving the α3/α4/α5 network of type IV collagen. Mutations in any of the COL4A3, COL4A4 or COL4A5 genes can lead to total or partial loss of this network. Males with mutations in the X-linked COL4A5 gene develop Alport syndrome with progressive renal disease and sometimes extra-renal disease. Females who are heterozygous for a COL4A5 mutation are considered to be carriers for X-linked Alport syndrome. Although their clinical course and GBM ultrastructural changes can sometimes mimic TBMN, more often it tends to be more progressive than usually seen in TBMN. Males or females who are heterozygous for COL4A3 or COL4A4 mutations usually manifest as TBMN, with nonprogressive hematuria, while those who are homozygous or combined heterozygotes develop autosomal-recessive Alport syndrome. Thus, individuals with TBMN can be considered to be carriers for autosomal-recessive Alport syndrome, but there remain some exceptions in which patients heterozygous for COL4A3 or COL4A4 mutations develop autosomal-dominant Alport syndrome. Distinguishing between all these groups of patients requires a combination of family history and a renal biopsy for electron microscopic examination of the GBM and immunohistochemical staining of the GBM for the α3, α4 and α5 chains of type IV collagen. Mutational analysis of the COL4A3, COL4A4, and COL4A5 genes, whenever it becomes available, will be a valuable adjunct to the diagnostic workup in these patients. Novel therapeutic approaches may one day provide a treatment or cure for these patients, avoiding the need for transplantation and dialysis.

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“…39,40 If VHL is restored in RCC lines by using variants that have been shown to retain HIF binding and degradation functions, matrix is still not assembled normally. 41 Based on these studies, we would have predicted that lack of VHL in podocytes should result in a thinner or perhaps "lacy" GBM such as that seen in Alport mice, 9,15 especially in view of the fact that podocytes are entirely responsible for synthesis of collagen ␣3␣4␣5(IV) of mature GBM. 4 Why the lack of podocyte VHL leads to apparently increased matrix is therefore unclear.…”

Section: Discussionmentioning

confidence: 99%

“…14 In contrast, heterozygous Col4␣3 ϩ/Ϫ mice have thinner GBMs and resemble human COL4A3 carriers with thin basement membrane nephropathy. 15 Many other renal diseases also display GBM modifications during the course of progression to fibrosis, including the thickened GBM of mesangial sclerosis 16 and diabetic nephropathy. 17 The tight regulation of GBM components led us to question what transcription factor systems might play a role in either the normal developmental isoform substitutions or the re-expression of matrix components during disease.…”

Section: Vascular Endothelial Growth Factor Which Is Critical For Blmentioning

confidence: 99%

Deletion of Von Hippel-Lindau in Glomerular Podocytes Results in Glomerular Basement Membrane Thickening, Ectopic Subepithelial Deposition of Collagen α1α2α1(IV), Expression of Neuroglobin, and Proteinuria

Steenhard

Isom

Stroganova

et al. 2010

The American Journal of Pathology

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Vascular endothelial growth factor, which is critical for blood vessel formation, is regulated by hypoxia inducible transcription factors (HIFs). A component of the E3 ubiquitin ligase complex, von Hippel-Lindau (VHL) facilitates oxygen-dependent polyubiquitination and proteasomal degradation of HIF␣ subunits. Hypothesizing that deletion of podocyte VHL would result in HIF␣ hyperstabilization, we crossed podocin promoter-Cre transgenic mice, which express Cre recombinase in podocytes beginning at the capillary loop stage of glomerular development, with floxed VHL mice. Vascular patterning and glomerular development appeared unaltered in progeny lacking podocyte VHL. However, urinalysis showed increased albumin excretion by 4 weeks when compared with wild-type littermates with several sever cases (>1000 g/ml). Many glomerular ultrastructural changes were seen in mutants, including focal subendothelial delamination and widespread podocyte foot process broadening, and glomerular basement membranes (GBMs) were significantly thicker in 16-week-old mutants compared with controls. Moreover, immunoelectron microscopy showed ectopic deposition of collagen ␣1␣2␣1(IV) in GBM humps beneath podocytes. Significant increases in the number of Ki-67-positive mesangial cells were also found, but glomerular WT1 expression was significantly decreased, signifying podocyte death and/or de-differentiation. Indeed, expression profiling of mutant glomeruli suggested a negative regulatory feedback loop involving the HIF␣ prolyl hydroxylase, Egln3. In addition, the brain oxygen-binding protein, Neuroglobin, was induced in mutant podocytes. We conclude that podocyte VHL is required for normal maintenance of podocytes, GBM composition and ultrastructure, and glomerular barrier properties.

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Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice

Cited by 43 publications

References 42 publications

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Alport Syndrome and Thin Basement Membrane Nephropathy

Deletion of Von Hippel-Lindau in Glomerular Podocytes Results in Glomerular Basement Membrane Thickening, Ectopic Subepithelial Deposition of Collagen α1α2α1(IV), Expression of Neuroglobin, and Proteinuria

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