Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model

Diping Wang, Gina M. Warner, Ping Yin, Bruce E. Knudsen, Jingfei Cheng, Kim A. Butters, Karen R. Lien, Catherine E. Gray, Vesna D Garovic, Lilach O Lerman, Stephen C Textor, Karl A Nath, Robert D. Simari, Joseph Peter Grande

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude thatp38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume304
Issue number7
DOIs
StatePublished - 2013

Fingerprint

Renal Artery Obstruction
p38 Mitogen-Activated Protein Kinases
Atrophy
Fibrosis
Kidney
CCR2 Receptors
Inflammation
Chronic Renal Insufficiency
Renal Artery
Extracellular Matrix
Up-Regulation
Collagen
Hypertension
Messenger RNA
SB 203580
Wounds and Injuries

Keywords

  • Atrophy
  • CCL2
  • CCR2
  • Fibrosis
  • Renal artery stenosis

ASJC Scopus subject areas

  • Physiology
  • Urology
  • Medicine(all)

Cite this

Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model. / Wang, Diping; Warner, Gina M.; Yin, Ping; Knudsen, Bruce E.; Cheng, Jingfei; Butters, Kim A.; Lien, Karen R.; Gray, Catherine E.; Garovic, Vesna D; Lerman, Lilach O; Textor, Stephen C; Nath, Karl A; Simari, Robert D.; Grande, Joseph Peter.

In: American Journal of Physiology - Renal Physiology, Vol. 304, No. 7, 2013.

Research output: Contribution to journalArticle

Wang, Diping ; Warner, Gina M. ; Yin, Ping ; Knudsen, Bruce E. ; Cheng, Jingfei ; Butters, Kim A. ; Lien, Karen R. ; Gray, Catherine E. ; Garovic, Vesna D ; Lerman, Lilach O ; Textor, Stephen C ; Nath, Karl A ; Simari, Robert D. ; Grande, Joseph Peter. / Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model. In: American Journal of Physiology - Renal Physiology. 2013 ; Vol. 304, No. 7.
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abstract = "Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70{\%} vs. 39{\%}, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude thatp38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.",
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AU - Wang, Diping

AU - Warner, Gina M.

AU - Yin, Ping

AU - Knudsen, Bruce E.

AU - Cheng, Jingfei

AU - Butters, Kim A.

AU - Lien, Karen R.

AU - Gray, Catherine E.

AU - Garovic, Vesna D

AU - Lerman, Lilach O

AU - Textor, Stephen C

AU - Nath, Karl A

AU - Simari, Robert D.

AU - Grande, Joseph Peter

PY - 2013

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N2 - Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude thatp38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

AB - Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-β-induced CCL2 upregulation. Based on these observations, we conclude thatp38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

KW - Atrophy

KW - CCL2

KW - CCR2

KW - Fibrosis

KW - Renal artery stenosis

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