title: TGF-beta1-induced glomerular disorder is associated with impaired concentrating ability mimicking primary glomerular disease with renal failure in man.
abstract: Transforming growth factor-beta1 (TGF-beta1) may play a major role in the pathogenesis of glomerulopathy and end-stage renal disease (ESRD). The aim of this study was to explore the functional consequences of localized overproduction of TGF-beta1 in relation to glomerular ultrastructure and the composition of the extracellular matrix (ECM) in the inner medulla. We used a transgenic mouse with overexpression of TGF-beta1 targeted to the juxtaglomerular apparatus (JGA) by the Ren-1c promoter. The kidney function was evaluated using urine production and metabolite excretion over a 24-hour period, glomerular filtration rate (GFR), and concentrating ability. The glomerular structure was analyzed in terms of volume, ie, the volume of the mesangium per glomerulus (Vv[mes/glom]) and the volume of the matrix per glomerulus (Vv[matrix/glom]), ECM per glomerulus, the area of the filtration surface, and the thickness of the peripheral basement membrane (PBM). Immunohistochemistry or in situ hybridization was used to examine the expression of aquaporin 2 (AQP2), plasminogen activator inhibitor-1 (PAI-1), and the composition of the ECM in the inner medulla. The mice exhibited polyuria, reduced concentrating ability, decreased GFR, and albuminuria paralleled by increased glomerular volume, with increased volume of ECM, decreased filtration surface, and thickening of the PBM being detectable between 1 and 2 months of age. The deposition of glomerular ECM was accompanied by increased levels of PAI-1. As estimated by excretion of Clara cell protein-1 (CC16) and lysozyme, tubular damage occurred only in older mice. Collagen Type I was deposited in the inner medulla in the presence of normal AQP2-expression in the collecting ducts. This study reached the following conclusions: (a) TGF-beta1 reduces the GFR and the glomerular filtration surface, (b) TGF-beta1 induces albuminuria in association with widening of the PBM, (c) expansion of the mesangial volume seems to precede the widening of the PBM, (d) TGF-beta1-induced accumulation of glomerular ECM is partly explained by increased PAI-1 expression, (e) Decreased concentrating ability and polyuria caused by accumulation of ECM in the inner medulla may be an early marker of glomerular diseases associated with increased expression of TGF-beta1 in man.
authors.affiliation: The Research Laboratory for Biochemical Pathology, The Institute of Experimental Clinical Research, Aarhus Kommunehospital, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Krag
authors.forename: R
authors.initials: R
authors.lastname: Osterby
authors.forename: Q
authors.initials: Q
authors.lastname: Chai
authors.forename: C B
authors.initials: CB
authors.lastname: Nielsen
authors.forename: C
authors.initials: C
authors.lastname: Hermans
authors.forename: L
authors.initials: L
authors.lastname: Wogensen
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000235:genetics; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004231:Diuresis / Q000235:genetics / Q000502:physiology; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007606:Juxtaglomerular Apparatus / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012016:Reference Values; D013552:Swine; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
chemical_list: C496023:AQP2 protein, human; C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D016212:Transforming Growth Factor beta; D000450:Aldosterone