title: Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.
abstract: Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
authors: Center for Cell Biology and Cancer Research, Albany Medical Center, NY, USA.
authors: Rohan
authors: R
authors: Samarakoon
authors: Division of Urology, Albany Medical College, NY, USA.
authors: Sevann
authors: S
authors: Helo
authors: Division of Urology, Albany Medical College, NY, USA.
authors: Amy D
authors: AD
authors: Dobberfuhl
authors: Center for Cell Biology and Cancer Research, Albany Medical Center, NY, USA.
authors: Nidah S
authors: NS
authors: Khakoo
authors: Department of Pathology, University Medical Centre Utrecht, The Netherlands.
authors: Lucas
authors: L
authors: Falke
authors: Center for Cell Biology and Cancer Research, Albany Medical Center, NY, USA.
authors: Jessica M
authors: JM
authors: Overstreet
authors: Department of Pathology, University Medical Centre Utrecht, The Netherlands.
authors: Roel
authors: R
authors: Goldschmeding
authors: Center for Cell Biology and Cancer Research, Albany Medical Center, NY, USA.
authors: Paul J
authors: PJ
authors: Higgins
mesh_terms: D000818:Animals; D017209:Apoptosis; D034341:Aristolochic Acids; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D034341:Aristolochic Acids; D004791:Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508960:TGFB1 protein, human; C495901:TP53 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D013311:Streptozocin; C000228:aristolochic acid I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: AAN; Akt; CTGF; PAI-1; PTEN; SMAD3; UUO; p53; renal fibrosis