title: Connective tissue growth factor modulates podocyte actin cytoskeleton and extracellular matrix synthesis and is induced in podocytes upon injury.
abstract: Structural changes of podocytes and retraction of their foot processes are a critical factor in the pathogenesis of minimal change nephritis and glomerulosclerosis. Here we tested, if connective tissue growth factor (CTGF) is involved in podocyte injury during acute and chronic puromycin aminonucleoside nephrosis (PAN) as animal models of minimal change nephritis, and focal segmental glomerulosclerosis, respectively. Rats were treated once (acute PAN) or for 13 weeks (chronic PAN). In both experimental conditions, CTGF and its mRNA were found to be highly upregulated in podocytes. The upregulation correlated with onset and duration of proteinuria in acute PAN, and glomerulosclerosis and high expression of glomerular fibronectin, and collagens I, III, and IV in chronic PAN. In vitro, treatment of podocytes with recombinant CTGF increased amount and density of actin stress fibers, the expression of actin-associated molecules such as podocalyxin, synaptopodin, ezrin, and actinin-4, and activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Moreover, we observed increased podocyte expression of mRNA for transforming growth factor (TGF)-β2, TGF-β receptor II, fibronectin, and collagens I, III, and IV. Treatment of cultured podocytes with puromycin aminonucleoside resulted in loss of actin stress fibers and cell death, effects that were partially prevented when CTGF was added to the culture medium. Depletion of CTGF mRNA in cultured podocytes by RNA interference reduced both the number of actin stress fibers and the expression of actin-associated molecules. We propose that the expression of CTGF is acutely upregulated in podocytes as part of a cellular attempt to repair structural changes of the actin cytoskeleton. When the damaging effects on podocyte structure and function persist chronically, continuous CTGF expression in podocytes is a critical factor that promotes progressive accumulation of glomerular extracellular matrix and glomerulosclerosis.
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fuchshofer
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ullmann
authors.forename: Ludwig F
authors.initials: LF
authors.lastname: Zeilbeck
authors.forename: Matti
authors.initials: M
authors.lastname: Baumann
authors.forename: Benjamin
authors.initials: B
authors.lastname: Junglas
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D009402:Nephrosis, Lipoid / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism; D011692:Puromycin Aminonucleoside; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor; D011692:Puromycin Aminonucleoside