Protein phosphatase Mg²⁺/Mn²⁺ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression (2024)

Tang, J., Goldschmeding, R., Samarakoon, R., & Higgins, P. J. (2020). Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression. FASEB Journal, 34(2), 2641-2656. https://doi.org/10.1096/fj.201902015RR

Tang, Jiaqi ; Goldschmeding, Roel ; Samarakoon, Rohan et al. / Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis : Novel mechanisms and co-dependency of expression. In: FASEB Journal. 2020 ; Vol. 34, No. 2. pp. 2641-2656.

@article{1ffa6ae81ece4b8bba12fc9610d19321,

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

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.",

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",

author = "Jiaqi Tang and Roel Goldschmeding and Rohan Samarakoon and Higgins, {Paul J.}",

note = "Funding Information: The authors thank Dr Wilhelm Kriz (University of Heidelberg, Heidelberg, Germany) for providing kidney tissue from Pax8-rtTA-tet-o-TGF-β1 double transgenic mice for IHC analyses. This study was supported by NIH grant GM057242 (PJH), a Capital Region Medical Research Institute grant (RS), and funding provided by the Graver Family Endowment and the Friedman, Butler and Roach Family Foundations (PJH). Funding Information: The authors thank Dr Wilhelm Kriz (University of Heidelberg, Heidelberg, Germany) for providing kidney tissue from Pax8‐rtTA‐tet‐o‐TGF‐β1 double transgenic mice for IHC analyses. This study was supported by NIH grant GM057242 (PJH), a Capital Region Medical Research Institute grant (RS), and funding provided by the Graver Family Endowment and the Friedman, Butler and Roach Family Foundations (PJH). Publisher Copyright: {\textcopyright} 2019 Federation of American Societies for Experimental Biology",

year = "2020",

month = feb,

day = "1",

doi = "10.1096/fj.201902015RR",

language = "English",

volume = "34",

pages = "2641--2656",

journal = "FASEB Journal",

issn = "0892-6638",

publisher = "FASEB",

number = "2",

}

Tang, J, Goldschmeding, R, Samarakoon, R & Higgins, PJ 2020, 'Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression', FASEB Journal, vol. 34, no. 2, pp. 2641-2656. https://doi.org/10.1096/fj.201902015RR

Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression. / Tang, Jiaqi; Goldschmeding, Roel; Samarakoon, Rohan et al.
In: FASEB Journal, Vol. 34, No. 2, 01.02.2020, p. 2641-2656.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis

T2 - Novel mechanisms and co-dependency of expression

AU - Tang, Jiaqi

AU - Goldschmeding, Roel

AU - Samarakoon, Rohan

AU - Higgins, Paul J.

N1 - Funding Information:The authors thank Dr Wilhelm Kriz (University of Heidelberg, Heidelberg, Germany) for providing kidney tissue from Pax8-rtTA-tet-o-TGF-β1 double transgenic mice for IHC analyses. This study was supported by NIH grant GM057242 (PJH), a Capital Region Medical Research Institute grant (RS), and funding provided by the Graver Family Endowment and the Friedman, Butler and Roach Family Foundations (PJH).Funding Information:The authors thank Dr Wilhelm Kriz (University of Heidelberg, Heidelberg, Germany) for providing kidney tissue from Pax8‐rtTA‐tet‐o‐TGF‐β1 double transgenic mice for IHC analyses. This study was supported by NIH grant GM057242 (PJH), a Capital Region Medical Research Institute grant (RS), and funding provided by the Graver Family Endowment and the Friedman, Butler and Roach Family Foundations (PJH). Publisher Copyright:© 2019 Federation of American Societies for Experimental Biology

PY - 2020/2/1

Y1 - 2020/2/1

N2 - 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.

AB - 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.

KW - CCN2/CTGF

KW - CKD

KW - epithelial dysfunction

KW - PAI-1

KW - TGF-β1

KW - Epithelial Cells/metabolism

KW - Humans

KW - Renal Insufficiency, Chronic/metabolism

KW - Tumor Suppressor Protein p53/metabolism

KW - Signal Transduction/drug effects

KW - Phosphoprotein Phosphatases/metabolism

KW - Kidney/metabolism

KW - PTEN Phosphohydrolase/metabolism

KW - Fibroblasts/metabolism

KW - Kidney Tubules/metabolism

KW - Protein Phosphatase 2C/metabolism

KW - Fibrosis/metabolism

KW - TGF-beta 1

KW - CTGF

KW - CCN2

UR - http://www.scopus.com/inward/record.url?scp=85078665569&partnerID=8YFLogxK

U2 - 10.1096/fj.201902015RR

DO - 10.1096/fj.201902015RR

M3 - Article

C2 - 31909517

AN - SCOPUS:85078665569

SN - 0892-6638

VL - 34

SP - 2641

EP - 2656

JO - FASEB Journal

JF - FASEB Journal

IS - 2

ER -

Tang J, Goldschmeding R, Samarakoon R, Higgins PJ. Protein phosphatase Mg2+/Mn2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression. FASEB Journal. 2020 Feb 1;34(2):2641-2656. doi: 10.1096/fj.201902015RR