Bone marrow transplantation rescues Alport mice.
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Animals↗
Biomedical subjects
Oliver Gross
Publications and source records attributed to Oliver Gross.
Chronic renal failure and shortened lifespan in COL4A3+/- mice: an animal model for thin basement membrane nephropathy.
A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.
Aging↗
Increased seroprevalence of parvovirus B 19 IgG in complex regional pain syndrome is not associated with antiendothelial autoimmunity.
The etiology of complex regional pain syndrome (CRPS) is unclear yet. Recently autoantibodies and antecedent viral infections have been discussed to be involved in the pathogenesis of CRPS. We investigated sera from 39 CRPS patients and healthy controls for parvovirus B19 IgG and the occurrence of antiendothelial autoantibodies (AECA). CRPS patients showed a higher seroprevalence of parvovirus B19 IgG than controls (p < 0.01). All CRPS 2 patients were positive. 10.2% of the CRPS patients and 10.0% of the controls had AECA (n.s.) and AECA were not associated with parvovirus B19 seropositivity. Our findings suggest the involvement of parvovirus B19, but not autoantibody-mediated endothelial cell damage, in the pathogenesis of CRPS.
Adult↗
[From the molecular genetics of Alport's syndrome to principles of organo-protection in chronic renal diseases].
BACKGROUND: Scarring is known to be the endpoint of most chronic kidney diseases. Therefore, prevention of renal fibrosis is a very important topic. The hereditary type IV collagen disease Alport's syndrome is a rare, but challenging cause of chronic renal fibrosis. PATHOGENESIS OF GLOMERULAR AND INTERSTITIAL RENAL FIBROSIS IN HUMANS: Increasing knowledge about the pathogenesis of Alport's syndrome may help to find principles of nephro-protection in chronic renal diseases. The defect gene in Alport's syndrome causes an altered assembly of extracellular matrix leading to a defect cell-matrix interaction and fibrosis. This scarring is regulated by comparable mechanisms as in diabetic nephropathy or chronic inflammatory renal diseases. NEPHRO-PROTECTION IN ANIMAL MODELS: By using an Alport animal model of chronic renal fibrosis, principles of nephro-protective therapies such as blockade of the renin-angiotensin system or the effect of HMG-CoA reductase inhibitors can be investigated. CURRENT AND FUTURE NEPHRO-PROTECTION IN HUMANS: The same model serves for evaluation of new organo-protective therapies such as vasopeptidase inhibitors, blockade of endothelin, chemokine and collagen receptors as well as stem cell therapy and their potential benefit for patients with chronic renal diseases.
Animals↗
Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease.
Human Alport disease is caused by a lack of the alpha3-, 4-, or 5-chain of type IV collagen (COL4A). Affected humans and COL4A3-deficient mice develop glomerulosclerosis and progressive renal fibrosis in the presence of interstitial macrophages, but their contribution to disease progression is under debate. This question was addressed by treating COL4A3-deficient mice with BX471, an antagonist of chemokine receptor 1 (CCR1) that is known to block interstitial leukocyte recruitment. Treatment with BX471 from weeks 6 to 10 of life improved survival of COL4A3-deficient mice, associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal Cll5 mRNA expression by reducing the number of interstitial CCL5-positive cells in inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and interstitial migration were not affected. Furthermore, in activated murine macrophages, BX471 completely blocked CCL3-induced CCL5 production. Thus, CCR1-mediated recruitment and local activation of macrophages contribute to disease progression in COL4A3-deficient mice. These data identify CCR1 as a potential therapeutic target for Alport disease or other progressive nephropathies associated with interstitial macrophage infiltrates.
Animals↗
Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome.
This study summarizes 47 novel mutations identified during routine molecular diagnostics for Alport syndrome. We detected 34 in COL4A5, the gene responsible for X-linked Alport syndrome, and 13 in COL4A3 and COL4A4, the genes responsible for autosomal recessive Alport syndrome. A high detection rate of 90% was achieved among patients with typical clinical symptoms and a characteristic family history in both X-linked and autosomal recessive forms, and it can be assumed that most relevant mutations have been identified. In numerous positively tested patients, genetic variations which are unknown were detected.
Collagen↗
Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688.
BACKGROUND: Chronic renal disease substantially increases the risk of cardiovascular events and death. Vasopeptidase inhibitors are known to show a strong antihypertensive effect. In the present study, we investigated the nephroprotective potential of the vasopeptidase inhibitor AVE7688 beyond its antihypertensive effects in a mouse model of progressive renal fibrosis. METHODS: COL4A3 -/- mice received 25 mg AVE7688 per kg body weight. Treatment was initiated in week 4 (early) and week 7 (late). Eight mice per group were sacrificed after 7.5 or 9.5 weeks, and serum levels of urea, systemic blood pressure, and proteinuria were measured. Renal tissue was investigated by routine histology, electron microscopy, immunohistochemistry, and Western blotting. Lifespan until death from renal fibrosis was monitored. RESULTS: Lifespan of treated mice increased by 143% (early therapy) and by 53% (late therapy) compared to untreated animals (172 +/- 19 vs. 109 +/- 15 vs. 71 +/- 6 days, P < 0.01). Untreated COL4A3 -/- mice did not develop severe hypertension (mean systolic blood pressure 116 +/- 14 vs. 111 +/- 9 mm Hg in wild-type mice), and both therapies mildly reduced systemic blood pressure (107 +/- 13 and 105 +/- 14 mm Hg, data not significant). AVE7688 decreased proteinuria from 12 +/- 3 g/L in untreated mice to 2 +/- 1 g/L (early) and to 4 +/- 1 g/L (late therapy, P < 0.05), as well as serum-urea from 247 +/- 27 to 57 +/- 10 and to 105 +/- 20 mmol/L (P < 0.05). Extent of fibrosis, inflammation, and profibrotic cytokines was reduced by AVE7688 therapy. CONCLUSION: The results indicate a strong nephroprotective effect of the vasopeptidase inhibitor in this animal model of progressive renal fibrosis. Besides the antihypertensive action of AVE7688, its antifibrotic, anti-inflammatory, and antiproteinuric effects demonstrated in the present study may serve as an important therapeutic option for chronic inflammatory and fibrotic diseases in man.
Animals↗
Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis.
BACKGROUND: Several studies have shown antifibrotic effects of angiotensin converting enzyme (ACE) inhibitors as well as of angiotensin receptor 1 (AT1) antagonists, however, prospective trials with clinical end points comparing these effects do not exist. COL4A3-/- mice develop a non-hypertensive progressive renal fibrosis. We used this animal model to compare the potential of ACE inhibitor vs AT1 antagonist to prevent renal fibrosis irrespective of blood pressure-dependent involvement by the renin system. METHODS: COL4A3-/- mice were treated with placebo, ramipril or candesartan. Blood pressure, proteinuria, serum urea and lifespan were monitored. Renal matrix was characterized by immuno-histochemistry, light and electron microscopy. Further biochemical analysis was provided using cDNA microarray and western blot techniques. RESULTS: Untreated mice died of renal failure after 71+/-6 days. Ramipril and candesartan both delayed onset and reduced the extent of proteinuria. Both had minor effects on blood pressure and postponed onset of uraemia. Ramipril increased lifespan by 111% to 150+/-21 days (P<0.01), whereas candesartan resulted in only a 38% prolongation to 98+/-16 days (P<0.01). Ramipril reduced glomerular and tubulo-interstitial fibrosis and numbers of activated fibroblasts to a greater extent than candesartan. Microarray and western blot analysis revealed a higher antifibrotic potential of ramipril in terms of downregulation of TGFbeta, connective tissue growth factor, metalloproteinases and extracellular matrix proteins. CONCLUSIONS: The results indicate an antifibrotic, nephroprotective effect of ACE inhibitors and AT1 antagonists in an animal model of progressive renal fibrosis. The greater antifibrotic effect of ramipril at the maximal therapeutic doses employed may not be explained by different antiproteinuric or blood pressure lowering properties, but by-in contrast to candesartan-its ability to hinder the proinflammatory, profibrotic activation of the angiotensin receptor 2.
Angiotensin II Type 1 Receptor Blockers↗
ARB: a software environment for sequence data.
The ARB (from Latin arbor, tree) project was initiated almost 10 years ago. The ARB program package comprises a variety of directly interacting software tools for sequence database maintenance and analysis which are controlled by a common graphical user interface. Although it was initially designed for ribosomal RNA data, it can be used for any nucleic and amino acid sequence data as well. A central database contains processed (aligned) primary structure data. Any additional descriptive data can be stored in database fields assigned to the individual sequences or linked via local or worldwide networks. A phylogenetic tree visualized in the main window can be used for data access and visualization. The package comprises additional tools for data import and export, sequence alignment, primary and secondary structure editing, profile and filter calculation, phylogenetic analyses, specific hybridization probe design and evaluation and other components for data analysis. Currently, the package is used by numerous working groups worldwide.
Data Display↗
DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria.
BACKGROUND: Type IV collagen in basement membranes is a ligand for the receptor tyrosine kinase discoidin domain receptor 1 (DDR1). DDR1 is expressed in renal cells and regulates cell adhesion and proliferation ex vivo. The interaction between type IV collagen and cell surface receptors is believed important for normal renal function as well as significant in chronic renal diseases and we therefore analyzed mice with a targeted deletion of DDR1. METHODS: Homozygous DDR1 knockout mice were compared to heterozygous and wild-type animals. The quantitative and qualitative amount of proteinuria was measured by urine-microelectrophoresis. Structural changes of the kidneys were determined by immunohistochemistry, light microscopy, and electron microscopy. RESULTS: Compared to heterozygous littermates, adult DDR1 knockout mice showed a selective middle- to high-molecular proteinuria of up to 0.3 g/L and urinary acanthocytes. There was no evidence of uremia with no change in serum urea in the first 9 months of age. Little apparent change in renal morphology was detected using light microscopy. However, electron microscopy showed a localized, subepithelial, mushroom-like isodense thickening of the glomerular basement membrane (GBM). Within these areas, a focal loss of the podocytic slit diaphragms occurred. CONCLUSION: The loss of cell-matrix communication in DDR1-deficient podocytes appears to result in excess synthesis of basement membrane proteins leading to disturbed anchorage of foot processes and disruption of the slit diaphragm. Our data suggest that the interaction between type IV collagen and DDR1 plays an important role in maintaining the structural integrity of the GBM.
Animals↗
Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome.
BACKGROUND: Alport syndrome (AS) is a common hereditary cause of end-stage renal failure in adolescence due to defects in type IV collagen genes. Molecular genetics allows early diagnosis, however, no preventive strategy can be offered. Using the COL4A3 -/- mouse, an animal model for human AS, we evaluated therapy with ramipril in mice. METHODS: One hundred and twenty-two Alport-mice were treated with 10 mg/kg/day ramipril added to drinking water. Proteinuria, serum-urea and lifespan were monitored. Renal matrix was characterized by immunohistochemistry, light- and electron microscopy, and Western blot. RESULTS: Untreated COL4A3 -/- mice died from renal failure after 71 +/- 6 days. Early therapy starting at four weeks of age and continuing to death delayed onset and reduced the extent of proteinuria. Uremia was postponed by three weeks in treated animals. Lifespan increased by more than 100% to 150 +/- 21 days (P < 0.01). In parallel, decreased deposition of extracellular matrix and lessened interstitial fibrosis as well as reduced amounts of renal transforming growth factor-beta1 (TGF-beta1) could be demonstrated. Late therapy starting at seven weeks decreased proteinuria, however, lifespan did not increase significantly. CONCLUSIONS: The results indicate an antiproteinuric and antifibrotic nephroprotective effect of ramipril in COL4A3 -/- mice is mediated by down-regulation of TGF-beta1. This effect in mice is enhanced by initiation of therapy during pre-symptomatic disease. The data in COL4A3 -/- mice as an animal-model for Alport syndrome suggest that ramipril might as well delay renal failure in humans with AS. Early diagnosis and preemptive treatment also may be crucial in humans.
Angiotensin-Converting Enzyme Inhibitors↗
Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome.
BACKGROUND: Alport syndrome (AS) is a common hereditary cause for end-stage renal failure due to a defect in type IV collagen genes. The molecular pathogenesis of benign familial haematuria (BFH) is not fully understood. Evidence from linkage analyses and mutation studies point to a role of the COL4A3/COL4A4 genes. The present study describes molecular changes of the COL4A4 gene that cause both diseases: autosomal recessive AS and BFH in a consanguine family with a 400-year-old history of haematuria. METHODS: RNA and DNA were isolated and analysed by RT-PCR, PCR, DNA and cDNA sequencing, and Southern blotting. Evaluation of family members comprised creatinine clearence, urine analysis, audiometry and past medical history. RESULTS: Forefathers of this family moved to a German village in the 17th century. Sporadic episodes of macrohaematuria have been reported ever since. Numerous family members with haematuria including the parents of the index family were heterozygous for a splice defect eliminating exon 25 from the alpha4(IV) cDNA. The daughter (15 years old, creatinine clearence 27 ml/min, proteinuria 5 g/day, hearing loss) was homozygous for the mutation, while the son (22 years old, creatinine clearance 68 ml/min, proteinuria 11 g/day, hearing loss, splitted and thickened glomerular basement membrane) was heterozygous. Further analysis showed a second mutation, an 18 bp in-frame deletion in exon 25, for which numerous family members were heterozygous, and both children were homozygous. CONCLUSIONS: The COL4A4 splice defect causes BFH-phenotype in heterozygous, and AS in homozygous state. The clinical spectrum of heterozygous individuals reaches from macrohaematuria, intermittent microhaematuria to isolated deafness. The 18 bp in-frame deletion aggravates the phenotype in the compound heterozygous son. These results give further evidence that BFH and autosomal AS are in fact both type IV collagen diseases.
Adolescent↗
X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study.
Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.
Adolescent↗
Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling.
BACKGROUND: Alport syndrome (AS) is a hereditary nephropathy characterized by progressive renal failure, hearing loss and ocular lesions. Numerous mutations of the COL4A5 gene encoding the alpha 5-chain of type IV collagen have been described, establishing the molecular cause of AS. The goal of the present study was to identify the genotype-phenotype correlations that are helpful in clinical counseling. COL4A5-mutations (n=267) in males were analysed including 23 German Alport families. METHODS: Exons of the COL4A5 gene were PCR-amplified and screened by Southern blot, direct sequencing or denaturing gradient gel electrophoresis. Phenotypes were obtained by questionnaires or extracted from 44 publications in the literature. Data were analysed by Kaplan-Meier statistics, chi(2) and Kruskal-Wallis tests. RESULTS: Genotype-phenotype data for 23 German Alport families are reported. Analysis of these data and of mutations published in the literature showed the type of mutation being a significant predictor of end-stage renal failure (ESRF) age. The patients' renal phenotypes could be grouped into three cohorts: (1) large rearrangements, frame shift, nonsense, and splice donor mutations had a mean ESRF age of 19.8+/-5.7 years; (2) non-glycine- or 3' glycine-missense mutations, in-frame deletions/insertions and splice acceptor mutations had a mean ESRF age of 25.7+/-7.2 years and fewer extrarenal symptoms; (3) 5' glycine substitutions had an even later onset of ESRF at 30.1+/-7.2 years. Glycine-substitutions occurred less commonly de novo than all other mutations (5.5% vs 13.9%). However, due to the evolutionary advantage of their moderate phenotype, they were the most common mutations. The intrafamilial phenotype of an individual mutation was found to be very consistent with regards to the manifestation of deafness, lenticonus and the time point of onset of ESRF. CONCLUSIONS: Knowledge of the mutation adds significant information about the progress of renal and extrarenal disease in males with X-linked AS. We suggest that the considerable prognostic relevance of a patient's genotype should be included in the classification of the Alport phenotype.
Base Sequence↗
X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.
Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.
Adult↗