Renal Disease in Marfan Syndrome

Sbar, G D; Venkataseshan, V S; Huang, Zhao; Marquet, E; Brunswick, J.; Churg, Jacob

doi:10.1159/000169017

Cited by 16 publications

(11 citation statements)

References 9 publications

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“…Thus, fibrillin-1 underexpression in mice does not seem to lead to defects in renal function, despite some reports of glomerular disease in patients with Marfan syndrome [12,22,24]. Sbar et al [24] described four Marfan patients with microhematuria and proteinuria. Renal biopsies of these patients revealed segmental increase in mesangial matrix with some sclerotic lesions.…”

Section: Discussionmentioning

confidence: 98%

“…Renal biopsies of these patients revealed segmental increase in mesangial matrix with some sclerotic lesions. The authors postulated that changes of microfibrillar arrangements could possibly lead to glomerular basement membrane alterations that might be the cause for microhematuria and proteinuria [24]. The reason that fibrillin-1-underexpressing mice do not show similar renal alterations to the Marfan patients might be that they still have enough normal fibrillin-1 to maintain glomerular structure and function; whereas, in Marfan syndrome, mutations in the fibrillin-1 gene generally lead to the expression of altered fibrillin-1 microfibrils and a lack of normal fibrillin-1 [21].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding its localization surrounding the glomerular capillaries, it seems likely that fibrillin-1 could contribute to the elastic strength and anchorage of the glomerular capillary tuft, a structure that is exposed to a high hydrostatic pressure to maintain a high ultrafiltration rate [28]. Several reports of different types of renal disease in Marfan patients have appeared [5,12,22,24,25], but it remains unknown whether these associations were coincidental or due to a systematic renal defect caused by the fibrillin-1 mutation. Studies have reported two models of fibrillin-1 gene-mutated mice [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the renal phenotype in a mouse model of Marfan syndrome

et al. 2004

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The microfibrillar protein fibrillin-1 is expressed abundantly in the vasculature and the glomerulus of the kidney. Mutations in the fibrillin-1 gene lead to Marfan syndrome. The most common complication of this disease is aortic dilatation due to elastic deficiencies of the vascular wall. Several case reports describe glomerular disease in patients with Marfan syndrome, and fibrillin-1 has been implicated in nephrogenesis. To study the role of fibrillin-1 in renal development and function, we characterized the renal phenotype of fibrillin-1-underexpressing mice. Kidney histology was evaluated by means of morphometry and stereology. Relative kidney weights, daily urine excretion, urinary albumin excretion, serum and urinary creatinine, as well as serum urea were not different than wild-type mice. Glomerular number and renal capillarization were normal. The size of the renal filtration surface was comparable in wild-type and fibrillin-1-underexpressing mice. There was no indication for glomerular, renal vascular, or tubulointerstitial injury. However, glomerular volume and mesangial area were reduced. No changes in glomerular cell numbers were detected, but the cellular volume of mesangial cells was significantly lower in glomeruli of fibrillin-1-underexpressing mice. Thus, despite the high abundance of fibrillin-1 in glomeruli of wild-type animals, underexpression of fibrillin-1 did not lead to functional deficiencies of the glomerulus. Alterations in renal histology were only subtle with a reduced glomerular volume and mesangial area likely due to a reduced mesangial cell volume.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of the renal phenotype in a mouse model of Marfan syndrome

et al. 2004

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“…38,39 Moreover, aneurysms and enhanced tissue fragility do also occur in Ehlers-Danlos syndrome that to some extent is mimicked by the phenotype of Bgn-/0 mice. 40,41 In both syndromes the occurrence of renal cysts has been reported, 42,43 which might be because of additional abnormalities in connective tissue based on the coincidence of other gene mutations. In addition, altered expression of decorin and biglycan has been described in patients with Marfan syndrome, suggesting a molecular relationship between these proteoglycans and fibrillin-1.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Fibrillin-1 by Biglycan and Decorin Is Important for Tissue Preservation in the Kidney During Pressure-Induced Injury

Schaefer

Mihálik

Bábelová

et al. 2004

The American Journal of Pathology

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There is growing evidence that the two small leucinerich proteoglycans biglycan and decorin regulate the assembly of connective tissues and alter cell behavior during development and pathological processes. In this study, we have used an experimental animal model of unilateral ureteral ligation and mice deficient in either biglycan or decorin. We discovered that pressure-induced injury to the wild-type kidneys led to overexpression of decorin, biglycan, fibrillin-1, and fibrillin-2. In contrast, in biglycan-deficient kidneys the overexpression of fibrillin-1 was markedly attenuated and this was associated with cystic dilatation of Bowman's capsule and proximal tubules. Notably, we found that in ligated kidneys from decorin-null mice, fibrillin-1 expression was initially enhanced to the same extent as in wild-type animals. However, long-term obstruction resulted in down-regulation of fibrillin-1 and concurrent cystic dilatation of Bowman's capsule in 33% of kidneys at 5 months after obstruction. In all of the genotypes, no differences in fibrillin-2 expression were observed. These in vivo data correlated with a significant induction of fibrillin-1 expression in renal fibroblasts and mesangial cells by recombinant biglycan and decorin. Biglycan and decorin belong to the family of small leucine-rich proteoglycans (SLRPs), which are characterized by core proteins with centrally located leucine-rich motifs flanked by cysteine clusters and by one (decorin) or two (biglycan) chondroitin/dermatan-sulfate side chains. SLRPs are primarily considered to play a role in collagen fibril formation and stability.

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“…The function of fibrillin-1 in the glomerular mesangium, however, is not known. Several case reports describing different types of glomerular disease in patients with Marfan syndrome have been published (1,11,17,18,22), but there is no evidence that this is more than a chance association. No systematic study on renal sequelae of Marfan syndrome has been performed so far.…”

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confidence: 99%

Role of fibrillin-1 in hypertensive and diabetic glomerular disease

Hartner¹,

Schaefer²,

Porst³

et al. 2006

American Journal of Physiology-Renal Physiology

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The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predisposes individuals to vascular damage in Marfan syndrome, but the role of fibrillin-1 in kidney disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive or diabetic glomerular disease. DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition. To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 mo of life. All DOCA-treated mgR/mgR mice died within 2 wk after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and their wild-type littermates displayed similar blood pressure levels, but albuminuria was significantly lower in mgR/+ than in wild-type mice after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than wild-type mice despite higher blood glucose levels in mgR/mgR and mgR/+ compared with wild-type mice. Blood pressure, blood glucose, and albuminuria did not differ among untreated mgR/mgR, mgR/+, and wild-type mice, respectively. In diabetic mgR/+ and mgR/mgR, but not in wild-type mice, an induction of glomerular decorin expression was observed. Thus underexpression of fibrillin-1 predisposes individuals to lethal aortic dissection in the presence of hypertension. On the other hand, albuminuria as a parameter of microvascular damage in hypertension and diabetes was ameliorated in fibrillin-1-underexpressing mice, possibly due to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease.

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Renal Disease in Marfan Syndrome

Cited by 16 publications

References 9 publications

Characterization of the renal phenotype in a mouse model of Marfan syndrome

Characterization of the renal phenotype in a mouse model of Marfan syndrome

Regulation of Fibrillin-1 by Biglycan and Decorin Is Important for Tissue Preservation in the Kidney During Pressure-Induced Injury

Role of fibrillin-1 in hypertensive and diabetic glomerular disease

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