title: Dynamic expression patterns of transforming growth factor-beta(2) and transforming growth factor-beta receptors in experimental glomerulonephritis.
abstract: Numerous studies have demonstrated the involvement of the transforming growth factor (TGF) isoform beta(1) in the pathogenesis of renal fibroproliferative diseases. Although in vitro studies suggest that TGF-beta(2) is equally potent to TGF-beta(1) in terms of its antimitogenic and fibrogenic effects, much less is known about the regulation of TGF-beta(2) in renal diseases associated with glomerular cell hyperplasia and matrix expansion. Here we investigated the glomerular expression patterns of TGF-beta(2) and of the TGF-beta receptors I, II, and III during the course of rat anti-Thy1.1 nephritis (days 2, 6, 12, and 56), a model characterized by transient mesangial hypercellularity and extracellular matrix accumulation. TGF-beta(2) exhibited dynamic changes in expression. Immunohistochemical double-staining of renal sections revealed that most TGF-beta(2)-positive cells in control glomeruli were podocytes with few TGF-beta(2)-positive mesangial cells. This staining pattern could also be observed in human kidney. On day 6 of anti-Thy1.1 nephritis both TGF-beta(2) positive podocytes and mesangial cells were more abundant. By western blot analysis of isolated glomeruli from nephritic rats, protein expression of TGF-beta(2) was upregulated tenfold over control glomeruli, peaking on day 6 of the disease. In cultured rat mesangial cells we found that the TGF-beta(2) and TGF-beta(1) isoforms were equally potent in terms of nuclear accumulation of phosphorylated Smad 2/3, inhibition of DNA synthesis, and induction of beta(1)-integrin and type I collagen protein synthesis. Protein expression of the TGF-beta receptor I was not detected by immunohistochemistry in control glomeruli but was markedly induced in the mesangium on day 6 of nephritis. Mesangial staining for TGF-beta receptors II and III was detected in normal kidneys. Expression of TGF-beta receptor II was strongly enhanced on days 6 and 12 of disease, while TGF-beta receptor III was upregulated only on day 6. In summary, we report marked yet transient upregulation of TGF-beta(2) protein and of TGF-beta receptors I, II, and III in glomerular cells during anti-Thy1.1 nephritis. These results are in keeping with the notion that TGF-beta(2) and its receptors participate in the pathogenesis and/or resolution of this transient form of glomerulonephritis.
authors.affiliation: Medizinische Klinik IV, Universität Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartner
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.forename: Roland
authors.initials: R
authors.lastname: Veelken
authors.forename: Harald O
authors.initials: HO
authors.lastname: Schöcklmann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2
chemical_list: D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2