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

• DOI: 10.1002/path.4538
• Publication Date: 2015-03-25T09:24:49Z
• Authors: Rohan Samarakoon; Sevann Helo; Amy D Dobberfuhl; Nidah S Khakoo; Lucas Falke; Jessica M Overstreet; Roel Goldschmeding; Paul J Higgins
• Keywords: Tensin

Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis diabetic ischaemic renal injury. However, potential role associated mechanisms progression kidney is unknown. Tubular interstitial expression was dramatically decreased several models injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury ureteral unilateral obstruction (UUO), correlating with Akt, p53 SMAD3 activation fibrosis. Stable silencing HK-2 human tubular epithelial cells induced dedifferentiation CTGF, PAI-1, vimentin, α-SMA fibronectin expression, compared to expressing control shRNA. Furthermore, knockdown stimulated p53(Ser15) phosphorylation, an accompanying decrease population density increase G1 cell cycle arrest. or gene pharmacological blockade partially suppressed fibrotic relieved growth inhibition orchestrated by deficiency PTEN. Similarly, shRNA suppression PAI-1 rescued loss-associated proliferative Moreover, TGFβ1-initiated further enhanced depletion. Combined TGFβ1 treatment potentiated death via p53-dependent pathways. Thus, loss initiates dysfunction SMAD3- p53-mediated induction, PAI-1-dependent arrest, cooperates induce profibrotic genes apoptosis.