title: TGF-beta1 regulates the PINCH-1-integrin-linked kinase-alpha-parvin complex in glomerular cells.
abstract: Glomerular damage is a major cause of renal failure. Recent studies suggest that a ternary protein complex that consists of PINCH-1, integrin-linked kinase, and alpha-parvin, cytoplasmic components of cell-extracellular matrix adhesions, plays pivotal roles in regulation of glomerular cell behavior. It is reported here that TGF-beta1, a key factor in the progression of glomerular failure, regulates the PINCH-1-integrin-linked kinase-alpha-parvin (PIP) complex formation in glomerular podocytes and mesangial cells. Treatment of podocytes with TGF-beta1 inhibited the PIP complex formation. Forced disruption of the PIP complex in podocytes activated p38 mitogen-activated protein kinase and promoted apoptosis. Importantly, inhibition of p38 mitogen-activated protein kinase, either with a chemical p38 inhibitor (SB202190) or with a dominant negative form of p38alpha, alleviates podocyte apoptosis that is induced by the disruption of the PIP complex. In contrast to an inhibitory role in podocytes, TGF-beta1 promotes the PIP complex formation in mesangial cells. Thus, TGF-beta1 regulates the PIP complex in a cell type-dependent manner. Because the PIP complex promotes glomerular mesangial matrix deposition and protects podocytes from apoptosis, the TGF-beta1-induced up- and downregulation of the PIP complex likely contribute to the pleiotropic effects of TGF-beta1 on different glomerular cell types and hence the progression of glomerular failure.
authors.affiliation: Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
authors.forename: Kyu Yong
authors.initials: KY
authors.lastname: Jung
authors.forename: Ka
authors.initials: K
authors.lastname: Chen
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
mesh_terms: D000185:Actinin / Q000737:chemistry / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D051379:Mice; D046912:Multiprotein Complexes; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D000185:Actinin; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000099200:Scaffold Protein ILK; C490232:Lims1 protein, mouse