Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

Frank Y. Ma, Yingjie Han, Elyce Ozols, Phyllis Chew, David A. Vesey, Glenda C. Gobe, Christudas Morais, Rink Jan Lohman, Jacky Y. Suen, David W. Johnson, David P. Fairlie, David J. Nikolic-Paterson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Aim: Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C–C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. Methods: Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2−/− and wild type (WT) littermate mice which were killed 7 days later. Non-experimental mice were controls. Results: Wild type mice exhibited a 5-fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM-1 and decreased α-Klotho expression) and tubular signalling (extracellular signal-regulated kinase phosphorylation) seen in WT UUO were not altered in Par2−/− UUO. In addition, macrophage infiltration, up-regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up-regulation of pro-inflammatory molecules (tumour necrosis factor, CCL2, interleukin-36α) in WT UUO kidney were unchanged in Par2−/− UUO. Finally, the accumulation of α-SMA+ myofibroblasts, deposition of collagen IV and expression of pro-fibrotic factors (CTGF, TGF-β1) were not different between WT and Par2−/− UUO mice. Conclusion: Protease-activated receptor 2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.

Original languageEnglish
Pages (from-to)983-991
Number of pages9
JournalNephrology
Volume24
Issue number9
DOIs
Publication statusPublished - Sep 2019

Keywords

  • extracellular signal-regulated kinase
  • in situ hybridization
  • macrophage
  • tubular epithelial cells

Cite this

Ma, Frank Y. ; Han, Yingjie ; Ozols, Elyce ; Chew, Phyllis ; Vesey, David A. ; Gobe, Glenda C. ; Morais, Christudas ; Lohman, Rink Jan ; Suen, Jacky Y. ; Johnson, David W. ; Fairlie, David P. ; Nikolic-Paterson, David J. / Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney. In: Nephrology. 2019 ; Vol. 24, No. 9. pp. 983-991.
@article{4e7ccac7420e469fbffceeb7f0fd83eb,
title = "Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney",
abstract = "Aim: Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C–C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. Methods: Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2−/− and wild type (WT) littermate mice which were killed 7 days later. Non-experimental mice were controls. Results: Wild type mice exhibited a 5-fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM-1 and decreased α-Klotho expression) and tubular signalling (extracellular signal-regulated kinase phosphorylation) seen in WT UUO were not altered in Par2−/− UUO. In addition, macrophage infiltration, up-regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up-regulation of pro-inflammatory molecules (tumour necrosis factor, CCL2, interleukin-36α) in WT UUO kidney were unchanged in Par2−/− UUO. Finally, the accumulation of α-SMA+ myofibroblasts, deposition of collagen IV and expression of pro-fibrotic factors (CTGF, TGF-β1) were not different between WT and Par2−/− UUO mice. Conclusion: Protease-activated receptor 2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.",
keywords = "extracellular signal-regulated kinase, in situ hybridization, macrophage, tubular epithelial cells",
author = "Ma, {Frank Y.} and Yingjie Han and Elyce Ozols and Phyllis Chew and Vesey, {David A.} and Gobe, {Glenda C.} and Christudas Morais and Lohman, {Rink Jan} and Suen, {Jacky Y.} and Johnson, {David W.} and Fairlie, {David P.} and Nikolic-Paterson, {David J.}",
year = "2019",
month = "9",
doi = "10.1111/nep.13635",
language = "English",
volume = "24",
pages = "983--991",
journal = "Nephrology",
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Ma, FY, Han, Y, Ozols, E, Chew, P, Vesey, DA, Gobe, GC, Morais, C, Lohman, RJ, Suen, JY, Johnson, DW, Fairlie, DP & Nikolic-Paterson, DJ 2019, 'Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney', Nephrology, vol. 24, no. 9, pp. 983-991. https://doi.org/10.1111/nep.13635

Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney. / Ma, Frank Y.; Han, Yingjie; Ozols, Elyce; Chew, Phyllis; Vesey, David A.; Gobe, Glenda C.; Morais, Christudas; Lohman, Rink Jan; Suen, Jacky Y.; Johnson, David W.; Fairlie, David P.; Nikolic-Paterson, David J.

In: Nephrology, Vol. 24, No. 9, 09.2019, p. 983-991.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

AU - Ma, Frank Y.

AU - Han, Yingjie

AU - Ozols, Elyce

AU - Chew, Phyllis

AU - Vesey, David A.

AU - Gobe, Glenda C.

AU - Morais, Christudas

AU - Lohman, Rink Jan

AU - Suen, Jacky Y.

AU - Johnson, David W.

AU - Fairlie, David P.

AU - Nikolic-Paterson, David J.

PY - 2019/9

Y1 - 2019/9

N2 - Aim: Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C–C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. Methods: Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2−/− and wild type (WT) littermate mice which were killed 7 days later. Non-experimental mice were controls. Results: Wild type mice exhibited a 5-fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM-1 and decreased α-Klotho expression) and tubular signalling (extracellular signal-regulated kinase phosphorylation) seen in WT UUO were not altered in Par2−/− UUO. In addition, macrophage infiltration, up-regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up-regulation of pro-inflammatory molecules (tumour necrosis factor, CCL2, interleukin-36α) in WT UUO kidney were unchanged in Par2−/− UUO. Finally, the accumulation of α-SMA+ myofibroblasts, deposition of collagen IV and expression of pro-fibrotic factors (CTGF, TGF-β1) were not different between WT and Par2−/− UUO mice. Conclusion: Protease-activated receptor 2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.

AB - Aim: Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C–C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. Methods: Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2−/− and wild type (WT) littermate mice which were killed 7 days later. Non-experimental mice were controls. Results: Wild type mice exhibited a 5-fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM-1 and decreased α-Klotho expression) and tubular signalling (extracellular signal-regulated kinase phosphorylation) seen in WT UUO were not altered in Par2−/− UUO. In addition, macrophage infiltration, up-regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up-regulation of pro-inflammatory molecules (tumour necrosis factor, CCL2, interleukin-36α) in WT UUO kidney were unchanged in Par2−/− UUO. Finally, the accumulation of α-SMA+ myofibroblasts, deposition of collagen IV and expression of pro-fibrotic factors (CTGF, TGF-β1) were not different between WT and Par2−/− UUO mice. Conclusion: Protease-activated receptor 2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.

KW - extracellular signal-regulated kinase

KW - in situ hybridization

KW - macrophage

KW - tubular epithelial cells

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U2 - 10.1111/nep.13635

DO - 10.1111/nep.13635

M3 - Article

C2 - 31314137

AN - SCOPUS:85070660641

VL - 24

SP - 983

EP - 991

JO - Nephrology

JF - Nephrology

SN - 1320-5358

IS - 9

ER -