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 viaSMAD3-mediated connective tissue growth factor and plasminogen activator inhibitor-1 upregulation. PPM1Astable suppression in normal rat kidney-49 renal fibroblasts, in contrast, promoted aSMAD3- dependent connective tissue growth factor and plasminogen activator inhibitor-1induced proliferative response. Paracrine factors secretedbyPPM1A-depletedepithelial cells augmentedfibroblast proliferation(>50%)compared with controls. PPM1Asuppression in renal cells further enhanced TGF-β1inducedSMAD3 phosphorylation and fibrotic gene expression, whereas PPM1A overexpression inhibited both responses. Moreover, phosphate tensin homolog on chromosome10depletion inhuman kidney-2 cells resulted in loss of expression and decreasednuclear 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. Lossofexpressionof protein phosphatase magnesium-dependent 1Aduring kidney injury promotes fibrotic maladaptive repair.