Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression

Jiaqi Tang, Roel Goldschmeding, Rohan Samarakoon*, Paul J. Higgins

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

PPM1A and PTEN emerged as novel suppressors of chronic kidney disease (CKD). Since loss of PPM1A and PTEN in the tubulointerstitium promotes fibrogenesis, defining molecular events underlying PPM1A/PTEN deregulation is necessary to develop expression rescue as novel therapeutic strategies. Here we identify TGF-β1 as a principle repressor of PPM1A, as conditional renal tubular-specific induction of TGF-β1 in mice dramatically downregulates kidney PPM1A expression. TGF-β1 similarly attenuates PPM1A and PTEN expression in human renal epithelial cells and fibroblasts, via a protein degradation mechanism by promoting their ubiquitination. A proteasome inhibitor MG132 rescues PPM1A and PTEN expression, even in the presence of TGF-β1, along with decreased fibrogenesis. Restoration of PPM1A or PTEN similarly limits SMAD3 phosphorylation and the activation of TGF-β1-induced fibrotic genes. Concurrent loss of PPM1A and PTEN levels in aristolochic acid nephropathy further suggests crosstalk between these repressors. PPM1A silencing in renal fibroblasts, moreover, results in PTEN loss, while PTEN stable depletion decreases PPM1A expression with acquisition of a fibroproliferative phenotype in each case. Transient PPM1A expression, conversely, elevates cellular PTEN levels while lentiviral PTEN introduction increases PPM1A expression. PPM1A and PTEN, therefore, co-regulate each other's relative abundance, identifying a previously unknown pathological link between TGF-β1 repressors, contributing to CKD.

Original languageEnglish
Pages (from-to)2641-2656
Number of pages16
JournalFASEB Journal
Volume34
Issue number2
DOIs
Publication statusPublished - 1 Feb 2020

Keywords

  • CCN2/CTGF
  • CKD
  • epithelial dysfunction
  • PAI-1
  • TGF-β1
  • Epithelial Cells/metabolism
  • Humans
  • Renal Insufficiency, Chronic/metabolism
  • Tumor Suppressor Protein p53/metabolism
  • Signal Transduction/drug effects
  • Phosphoprotein Phosphatases/metabolism
  • Kidney/metabolism
  • PTEN Phosphohydrolase/metabolism
  • Fibroblasts/metabolism
  • Kidney Tubules/metabolism
  • Protein Phosphatase 2C/metabolism
  • Fibrosis/metabolism
  • TGF-beta 1
  • CTGF
  • CCN2

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