title: Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy.
abstract: Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (α3 and α5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the α1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes.
authors.affiliation: Department of Neuroanatomy, Medical Faculty Mannheim, University Heidelberg, Germany; wilhelm.kriz@urz.uni-heidelberg.de.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Kriz
authors.affiliation: Department of Neuroanatomy, Medical Faculty Mannheim, University Heidelberg, Germany.|Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Jana
authors.initials: J
authors.lastname: Löwen
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Federico
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: van den Born
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gröne
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Hermann Josef
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D018171:Agrin / Q000032:analysis; D001324:Autoantigens / Q000032:analysis; D001706:Biopsy; D060833:Cellular Microenvironment; D024141:Collagen Type IV / Q000032:analysis; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D050533:Glomerular Basement Membrane / Q000737:chemistry / Q000648:ultrastructure*; D005920:Glomerular Mesangium / Q000737:chemistry / Q000648:ultrastructure*; D019812:Heparan Sulfate Proteoglycans / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D046529:Microscopy, Electron, Transmission; D050199:Podocytes / Q000737:chemistry / Q000648:ultrastructure*; D012598:Sclerosis
chemical_list: D018171:Agrin; D001324:Autoantigens; C547475:COL4A1 protein, human; C478159:COL4A5 protein, human; D024141:Collagen Type IV; D019812:Heparan Sulfate Proteoglycans; C057112:type IV collagen alpha3 chain; C071927:perlecan
keywords: production of mesangial matrix; resumption of embryonic GBM synthesis; turnover of GBM components