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      Alport Syndrome and Thin Basement Membrane Nephropathy

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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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          Most cited references 29

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          Bone marrow contributes to renal parenchymal turnover and regeneration.

          In order to establish whether extra-renal cells contribute to the turnover and repair of renal tissues, this study examined kidneys of female mice that had received a male bone marrow transplant and kidney biopsies from male patients who had received kidney transplants from female donors. By using in situ hybridization to detect Y-chromosomes it could be demonstrated that circulating stem cells frequently engraft into the kidney and differentiate into renal parenchymal cells. In the human renal grafts it was confirmed that some of the recipient-derived cells within the kidney exhibited a tubular epithelial phenotype, by combining in situ hybridization with immunostaining for the epithelial markers CAM 5.2 and the lectin Ulex europaeus. Female mouse recipients of male bone marrow grafts showed co-localization of Y-chromosomes and tubular epithelial markers Ricinus communis and Lens culinaris, and a specific cytochrome P450 enzyme (CYP1A2) indicating an appropriate functional capability of clustered newly formed marrow-derived tubular epithelial cells. Y-chromosome-containing cells were observed within glomeruli, with morphology and location appropriate for podocytes. Within the murine kidney, these Y-chromosome-positive cells were negative for the mouse macrophage marker F4/80 antigen and leukocyte common antigen, but were vimentin-positive. The presence of bone marrow-derived cells was noted in both histologically normal mouse kidneys and in human transplanted kidneys suffering damage from a variety of causes. These data indicate that bone marrow cells contribute to both normal turnover of renal epithelia and regeneration after damage, and it is suggested that this could be exploited therapeutically. Copyright 2001 John Wiley & Sons, Ltd.
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            Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice.

            Multipotent mesenchymal stem or stromal cells (MSC) have shown to improve outcome of acute renal injury models, but whether MSC can delay renal failure in chronic kidney disease is not known. We injected primary MSC or saline into mice that lack the alpha3-chain of type IV collagen (COL4A3), a model of chronic kidney disease with close similarities to human Alport disease. Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice. However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections. Although MSC were found to localize to kidneys of COL4A3-deficient mice after injection, differentiation into renal cells was not detected. However, MSC expressed growth factors, that is, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 under basal culture conditions. In fact, VEGF mRNA levels were increased in kidneys of MSC-injected COL4A3-deficient mice and MSC supernatants enhance endothelial cell proliferation in vitro. Thus, weekly injections with MSC prevent loss of peritubular capillaries possibly owing to local production of growth factors rather than by differentiation into renal cells. The maintenance of interstitial vasculature is associated with less interstitial fibrosis but, is insufficient to delay renal failure and survival of COL4A3-deficient mice.
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              Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches

               JR Sanes,  JH Miner (1994)
              Collagen IV is a major component of vertebrate basal laminae (BLs). Studies in humans have revealed a family of genes encoding alpha 1- alpha 6 collagen IV chains and implicated alpha 3-alpha 6 in disease processes (Goodpasture and Alport syndromes and diffuse leiomyomatosis). To extend studies of these components to an experimentally accessible animal, we cloned cDNAs encoding partial collagen alpha 3, alpha 4, and alpha 5(IV) chains from the mouse. Ribonuclease protection assays showed that all three genes were expressed at highest levels in kidney and lung; alpha 5(IV) was also expressed at high levels in heart. We then made antibodies specific for each collagen IV chain. Immunohistochemical studies of several tissues revealed many combinations of collagen IV chains; however, alpha 3 and alpha 4 (IV) were always coexpressed, and only appeared in BLs that were alpha 5(IV) positive. The alpha 3-alpha 5(IV) chains were frequently but not exclusively associated with the S (beta 2) chain of laminin, as were the alpha 1, 2 (IV) collagen chains with laminin B1 (beta 1). An analysis of developing rat kidney BLs showed that newly formed (S-shaped) nephrons harbored collagen alpha 1 and alpha 2(IV) and laminin B1; maturing (capillary loop stage) BLs contained collagen alpha 1-alpha 5(IV) and laminin B1 and S-laminin; and mature glomerular BLs contained mainly collagen alpha 3-alpha 5(IV) and S-laminin. Thus, collagen alpha 1 and alpha 2(IV) and laminin B1 appear to be fetal components of the glomerular BL, and there is a developmental switch to collagen alpha 3-alpha 5(IV) and S-laminin expression.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                June 2007
                06 June 2007
                : 106
                : 2
                : c82-c88
                aDivision of Pathology, Hospital for Sick Children, and bDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ont., Canada
                101802 Nephron Clin Pract 2007;106:c82–c88
                © 2007 S. Karger AG, Basel

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                References: 40, Pages: 1


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