Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
FASEB J
2016 Oct 01;3010:3308-3320. doi: 10.1096/fj.201500105R.
Show Gene links
Show Anatomy links
Loss of expression of protein phosphatase magnesium-dependent 1A during kidney injury promotes fibrotic maladaptive repair.
Samarakoon R
,
Rehfuss A
,
Khakoo NS
,
Falke LL
,
Dobberfuhl AD
,
Helo S
,
Overstreet JM
,
Goldschmeding R
,
Higgins PJ
.
???displayArticle.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.
Boor,
Renal fibrosis: novel insights into mechanisms and therapeutic targets.
2010, Pubmed
Boor,
Renal fibrosis: novel insights into mechanisms and therapeutic targets.
2010,
Pubmed
Bu,
Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-beta/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway.
2008,
Pubmed
Chevalier,
Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy.
2009,
Pubmed
Couser,
The contribution of chronic kidney disease to the global burden of major noncommunicable diseases.
2011,
Pubmed
Dendooven,
Loss of endogenous bone morphogenetic protein-6 aggravates renal fibrosis.
2011,
Pubmed
Duffield,
Host responses in tissue repair and fibrosis.
2013,
Pubmed
Dvashi,
Protein phosphatase magnesium dependent 1A governs the wound healing-inflammation-angiogenesis cross talk on injury.
2014,
Pubmed
Falke,
A perspective on anti-CCN2 therapy for chronic kidney disease.
2014,
Pubmed
Friedman,
Therapy for fibrotic diseases: nearing the starting line.
2013,
Pubmed
Fukasawa,
Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury.
2006,
Pubmed
Fukasawa,
Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice.
2004,
Pubmed
Gökmen,
The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review.
2013,
Pubmed
Itoh,
Negative regulation of TGF-beta receptor/Smad signal transduction.
2007,
Pubmed
Jha,
Chronic kidney disease: global dimension and perspectives.
2013,
Pubmed
Lan,
Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model.
2003,
Pubmed
Lin,
PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.
2006,
Pubmed
Loeffler,
Transforming growth factor-β and the progression of renal disease.
2014,
Pubmed
Massagué,
TGFβ signalling in context.
2012,
Pubmed
Overstreet,
Tumor suppressor ataxia telangiectasia mutated functions downstream of TGF-β1 in orchestrating profibrotic responses.
2015,
Pubmed
Overstreet,
Redox control of p53 in the transcriptional regulation of TGF-β1 target genes through SMAD cooperativity.
2014,
Pubmed
Perico,
Chronic kidney disease: a research and public health priority.
2012,
Pubmed
Samarakoon,
Redox-induced Src kinase and caveolin-1 signaling in TGF-β1-initiated SMAD2/3 activation and PAI-1 expression.
2011,
Pubmed
Samarakoon,
TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis.
2012,
Pubmed
Samarakoon,
Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species.
2013,
Pubmed
Samarakoon,
Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.
2015,
Pubmed
Samarakoon,
TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities.
2013,
Pubmed
Samarakoon,
Integration of non-SMAD and SMAD signaling in TGF-beta1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells.
2008,
Pubmed
Strutz,
New insights into mechanisms of fibrosis in immune renal injury.
2003,
Pubmed
Yang,
Pathophysiology of acute kidney injury to chronic kidney disease: maladaptive repair.
2011,
Pubmed
Yang,
Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta1 signaling.
2003,
Pubmed
Yang,
Delayed re-epithelialization in Ppm1a gene-deficient mice is mediated by enhanced activation of Smad2.
2011,
Pubmed
Yang,
Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
2010,
Pubmed
Zeisberg,
BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.
2003,
Pubmed
Zhou,
Mechanism of chronic aristolochic acid nephropathy: role of Smad3.
2010,
Pubmed
