title: Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.
abstract: Protein phosphatase magnesium-dependent-1A (PPM1A) dephosphorylates SMAD2/3, which suppresses TGF-β signaling in keratinocytes and during Xenopus development; however, potential involvement of PPM1A in chronic kidney disease is unknown. PPM1A expression was dramatically decreased in the tubulointerstitium in obstructive and aristolochic acid nephropathy, which correlates with progression of fibrotic disease. Stable silencing of PPM1A in human kidney-2 human renal epithelial cells increased SMAD3 phosphorylation, stimulated expression of fibrotic genes, induced dedifferentiation, and orchestrated epithelial cell-cycle arrest via SMAD3-mediated connective tissue growth factor and plasminogen activator inhibitor-1 up-regulation. PPM1A stable suppression in normal rat kidney-49 renal fibroblasts, in contrast, promoted a SMAD3-dependent connective tissue growth factor and plasminogen activator inhibitor-1-induced proliferative response. Paracrine factors secreted by PPM1A-depleted epithelial cells augmented fibroblast proliferation (>50%) compared with controls. PPM1A suppression in renal cells further enhanced TGF-β1-induced SMAD3 phosphorylation and fibrotic gene expression, whereas PPM1A overexpression inhibited both responses. Moreover, phosphate tensin homolog on chromosome 10 depletion in human kidney-2 cells resulted in loss of expression and decreased nuclear levels of PPM1A, which enhanced SMAD3-mediated fibrotic gene induction and growth arrest that were reversed by ectopic PPM1A expression. Thus, phosphate tensin homolog on chromosome 10 is an upstream regulator of renal PPM1A deregulation. These findings establish PPM1A as a novel repressor of the SMAD3 pathway in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.-Samarakoon, R., Rehfuss, A., Khakoo, N. S., Falke, L. L., Dobberfuhl, A. D., Helo, S., Overstreet, J. M., Goldschmeding, R., Higgins, P. J. Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical Center, Albany, New York, USA; samarar@mail.amc.edu.
authors.forename: Rohan
authors.initials: R
authors.lastname: Samarakoon
authors.affiliation: Division of Urology, Albany Medical Center, Albany, New York, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rehfuss
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical Center, Albany, New York, USA.
authors.forename: Nidah S
authors.initials: NS
authors.lastname: Khakoo
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Lucas L
authors.initials: LL
authors.lastname: Falke
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California, USA; and.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Dobberfuhl
authors.affiliation: Division of Urology, Albany Medical Center, Albany, New York, USA.
authors.forename: Sevann
authors.initials: S
authors.lastname: Helo
authors.affiliation: Division of Nephrology and Hypertension, Vanderbilt Medical School, Nashville, Tennessee, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Overstreet
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical Center, Albany, New York, USA; higginp@mail.amc.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Higgins
mesh_terms: D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000293:injuries / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein; D055513:Connective Tissue Growth Factor; C000607456:PPM1A protein, human; D000071636:Protein Phosphatase 2C; D008274:Magnesium
keywords: CTGF; PAI-1; PTEN; TGF-β; renal fibrosis