PAI-1 induction during kidney injury promotes fibrotic epithelial dysfunction via deregulation of klotho, p53, and TGF-beta 1-receptor signaling
Gifford, Cody C.; Lian, Fei; Tang, Jiaqi; Costello, Angelica; Goldschmeding, Roel; Samarakoon, Rohan; Higgins, Paul J.
(2021) FASEB Journal, volume 35, issue 7, pp. 1 - 17
(Article)
Abstract
Renal fibrosis leads to chronic kidney disease, which affects over 15% of the U.S. population. PAI-1 is highly upregulated in the tubulointerstitial compartment in several common nephropathies and PAI-1 global ablation affords protection from fibrogenesis in mice. The precise contribution of renal tubular PAI-1 induction to disease progression, however, is
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unknown and surprisingly, appears to be independent of uPA inhibition. Human renal epithelial (HK-2) cells engineered to stably overexpress PAI-1 underwent dedifferentiation (E-cadherin loss, gain of vimentin), G2/M growth arrest (increased p-Histone3, p21), and robust induction of fibronectin, collagen-1, and CCN2. These cells are also susceptible to apoptosis (elevated cleaved caspase-3, annexin-V positivity) compared to vector controls, demonstrating a previously unknown role for PAI-1 in tubular dysfunction. Persistent PAI-1 expression results in a loss of klotho expression, p53 upregulation, and increases in TGF-βRI/II levels and SMAD3 phosphorylation. Ectopic restoration of klotho in PAI-1-transductants attenuated fibrogenesis and reversed the proliferative defects, implicating PAI-1 in klotho loss in renal disease. Genetic suppression of p53 reversed the PA1-1-driven maladaptive repair, moreover, confirming a pathogenic role for p53 upregulation in this context and uncovering a novel role for PAI-1 in promoting renal p53 signaling. TGF-βRI inhibition also attenuated PAI-1-initiated epithelial dysfunction, independent of TGF-β1 ligand synthesis. Thus, PAI-1 promotes tubular dysfunction via klotho reduction, p53 upregulation, and activation of the TGF-βRI-SMAD3 axis. Since klotho is an upstream regulator of both PAI-1-mediated p53 induction and SMAD3 signaling, targeting tubular PAI-1 expression may provide a novel, multi-level approach to the therapy of CKD.
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Keywords: cell cycle arrest, chronic kidney disease, epithelial dysfunction, klotho, obstructive nephropathy, p53, PAI-1, renal fibrosis, TGF-β1, TGF-beta 1, Up-Regulation/physiology, Humans, Transforming Growth Factor beta1/metabolism, Renal Insufficiency, Chronic/metabolism, Tumor Suppressor Protein p53/metabolism, Kidney/metabolism, Fibroblasts/metabolism, Klotho Proteins, Gene Expression Regulation/physiology, Plasminogen Activator Inhibitor 1/metabolism, Smad3 Protein/metabolism, Cell Line, Epithelial Cells/metabolism, Signal Transduction, Glucuronidase/metabolism, Phosphorylation/physiology, Fibrosis/metabolism, Genetics, Molecular Biology, Biochemistry, Biotechnology, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0892-6638
Publisher: FASEB
Note: Funding Information: This study was supported by NIH Grant GM057242 to PJH, a Capital District Medical Research Institute Grant to RS, the Friedman Family Research Fund, the Charlotte Graver Foundation, the John Faunce & Alicia Tracy Roach Fund, the Edith Dickstein & Sylvan Kessler Estate Foundation, the Butler Family Mesothelioma Research Fund, and Mueller Family Cancer Foundation 2+ 2+ Funding Information: This study was supported by NIH Grant GM057242 to PJH, a Capital District Medical Research Institute Grant to RS, the Friedman Family Research Fund, the Charlotte Graver Foundation, the John Faunce & Alicia Tracy Roach Fund, the Edith Dickstein & Sylvan Kessler Estate Foundation, the Butler Family Mesothelioma Research Fund, and Mueller Family Cancer Foundation. Publisher Copyright: © 2021 Federation of American Societies for Experimental Biology © 2021 Federation of American Societies for Experimental Biology.
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