title: Transforming growth factor-β inhibits cystogenesis in human autosomal dominant polycystic kidney epithelial cells.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and characterized by the formation of multiple fluid-filled cysts in the kidneys. It is believed that environmental factors may play an important role in the disease progression. However, the molecular identity of autocrine/paracrine factors influencing cyst formation is largely unknown. In this study, we identified transforming growth factor-β2 (TGF-β2) secreted by normal human kidney (NHK) and ADPKD cells as an inhibitor of cystogenesis in 3D culture system using ADPKD cells from human kidneys. TGF-β2 was identified in conditioned media (CM) of NHK and ADPKD cells as a latent factor activated by heat in vitro. While all TGF-β isoforms recombinant proteins (TGF-β1, -β2, or -β3) displayed a similar inhibitory effect on cyst formation, TGF-β2 was the predominant isoform detected in CM. The involvement of TGF-β2 in the suppression of cyst formation was demonstrated by using a TGF-β2 specific blocking antibody and a TGF-β receptor I kinase inhibitor. TGF-β2 inhibited cyst formation by a mechanism other than activation of p38 mitogen-activated protein (MAP) kinase that mediated cell death in ADPKD cells. Further, we found that TGF-β2 modulated expression of various genes involved in cell-cell and cell-matrix interactions and extracellular matrix proteins that may play a role in the regulation of cystogenesis. Collectively, our results suggest that TGF-β2 secreted by renal epithelial cells may be an inhibitor of cystogenesis influencing the progression of ADPKD.
authors.affiliation: Department of Pediatrics, Section of Nephrology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 73104, USA.
authors.forename: Dorit
authors.initials: D
authors.lastname: Elberg
authors.forename: Siddarth
authors.initials: S
authors.lastname: Jayaraman
authors.forename: Martin A
authors.initials: MA
authors.lastname: Turman
authors.forename: Gerard
authors.initials: G
authors.lastname: Elberg
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D017077:Culture Media, Conditioned; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I