ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2016
Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- Involvement of c-Myc/WWP1/TRIM65 Axis in Renal Fibrosis.Biomolecules · 2026Article
- TGF‑β/Smad signaling in chronic kidney disease: Exploring post‑translational regulatory perspectives (Review).Molecular medicine reports · 2024Review
- Therapeutic potential for renal fibrosis by targeting Smad3-dependent noncoding RNAs.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes.JCI insight · 2023Article
- A comprehensive overview of PPM1A: From structure to disease.Experimental biology and medicine (Maywood, N.J.) · 2022Review
- PAI-1 induction during kidney injury promotes fibrotic epithelial dysfunction via deregulation of klotho, p53, and TGF-β1-receptor signaling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Human ucMSCs seeded in a decellularized kidney scaffold attenuate renal fibrosis by reducing epithelial-mesenchymal transition via the TGF-β/Smad signaling pathway.Pediatric research · 2020Article
- TGF-β1-p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Review
- Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney diseaseFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Review
- Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program.Advances in wound care · 2017Review
- An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature.International journal of molecular sciences · 2017Review
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Authors and funding
9 authors at 5 institutions in 2 countries.
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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.
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