Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.

Samarakoon R, Helo S, Dobberfuhl AD, Khakoo NS, Falke L, Overstreet JM, Goldschmeding R, Higgins PJ
J Pathol. 2015 236 (4): 421-32

PMID: 25810340 · PMCID: PMC4509814 · DOI:10.1002/path.4538

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.

Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MeSH Terms (25)

Animals Apoptosis Aristolochic Acids Cell Cycle Checkpoints Cell Line Cell Proliferation Disease Models, Animal Enzyme Inhibitors Fibrosis Gene Expression Regulation Humans Kidney Diseases Kidney Tubules Male Mice, Inbred C57BL Plasminogen Activator Inhibitor 1 PTEN Phosphohydrolase RNA Interference Signal Transduction Smad3 Protein Streptozocin Transfection Transforming Growth Factor beta1 Tumor Suppressor Protein p53 Ureteral Obstruction

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