Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney

Yingjie Han, Takao Masaki, Lynette A. Hurst, Yohei Ikezumi, James M. Trzaskos, Robert C. Atkins, David J. Nikolic-Paterson

Research output: Contribution to journalArticle

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Abstract

Aim: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney. Methods: Unilateral ureteric obstruction was induced in C57BL/6J mice which then received an ERK inhibitor drug (U0126 100 mg/kg t.i.d.), vehicle (DMSO) or no treatment, starting at day 2 after unilateral ureteric obstruction surgery and continuing until animals were killed on day 5. Cell proliferation was assessed by uptake of bromodeoxyuridine (BrdU). Results: In normal mice, phosphorylation (activation) of ERK (p-ERK) was restricted to collecting ducts. Western blotting identified a marked increase in p-ERK in the obstructed kidney in the no-treatment and vehicle-treated groups. Immunostaining showed strong p-ERK staining in many tubules and in interstitial cells. U0126 treatment inhibited ERK phosphorylation as assessed by western blot and immunostaining. The number of BrdU+ cortical tubular cells was reduced by vehicle treatment but was not further changed by U0126 treatment. In contrast, interstitial cell proliferation in the obstructed kidney was unaltered by vehicle treatment, but this was significantly inhibited by U0126. This was associated with a reduction in interstitial macrophage accumulation, but no effect was seen upon interstitial accumulation of α-SMA+ myofibroblasts. Renal fibrosis, as assessed by collagen deposition, was unaffected by U0126 or vehicle treatment. Conclusion: These studies show that accumulation of interstitial macrophages in the obstructed kidney is, in part, dependent upon the ERK signalling pathway.

Original languageEnglish
Pages (from-to)411-418
Number of pages8
JournalNephrology
Volume13
Issue number5
DOIs
Publication statusPublished - 01-08-2008

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Extracellular Signal-Regulated MAP Kinases
Macrophages
Kidney
Cell Proliferation
Bromodeoxyuridine
Intercellular Signaling Peptides and Proteins
Western Blotting
Phosphorylation
Myofibroblasts
Kidney Diseases
Dimethyl Sulfoxide
Inbred C57BL Mouse
Fibrosis
Collagen
Animal Models
U 0126
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Han, Yingjie ; Masaki, Takao ; Hurst, Lynette A. ; Ikezumi, Yohei ; Trzaskos, James M. ; Atkins, Robert C. ; Nikolic-Paterson, David J. / Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney. In: Nephrology. 2008 ; Vol. 13, No. 5. pp. 411-418.
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abstract = "Aim: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney. Methods: Unilateral ureteric obstruction was induced in C57BL/6J mice which then received an ERK inhibitor drug (U0126 100 mg/kg t.i.d.), vehicle (DMSO) or no treatment, starting at day 2 after unilateral ureteric obstruction surgery and continuing until animals were killed on day 5. Cell proliferation was assessed by uptake of bromodeoxyuridine (BrdU). Results: In normal mice, phosphorylation (activation) of ERK (p-ERK) was restricted to collecting ducts. Western blotting identified a marked increase in p-ERK in the obstructed kidney in the no-treatment and vehicle-treated groups. Immunostaining showed strong p-ERK staining in many tubules and in interstitial cells. U0126 treatment inhibited ERK phosphorylation as assessed by western blot and immunostaining. The number of BrdU+ cortical tubular cells was reduced by vehicle treatment but was not further changed by U0126 treatment. In contrast, interstitial cell proliferation in the obstructed kidney was unaltered by vehicle treatment, but this was significantly inhibited by U0126. This was associated with a reduction in interstitial macrophage accumulation, but no effect was seen upon interstitial accumulation of α-SMA+ myofibroblasts. Renal fibrosis, as assessed by collagen deposition, was unaffected by U0126 or vehicle treatment. Conclusion: These studies show that accumulation of interstitial macrophages in the obstructed kidney is, in part, dependent upon the ERK signalling pathway.",
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Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney. / Han, Yingjie; Masaki, Takao; Hurst, Lynette A.; Ikezumi, Yohei; Trzaskos, James M.; Atkins, Robert C.; Nikolic-Paterson, David J.

In: Nephrology, Vol. 13, No. 5, 01.08.2008, p. 411-418.

Research output: Contribution to journalArticle

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T1 - Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney

AU - Han, Yingjie

AU - Masaki, Takao

AU - Hurst, Lynette A.

AU - Ikezumi, Yohei

AU - Trzaskos, James M.

AU - Atkins, Robert C.

AU - Nikolic-Paterson, David J.

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N2 - Aim: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney. Methods: Unilateral ureteric obstruction was induced in C57BL/6J mice which then received an ERK inhibitor drug (U0126 100 mg/kg t.i.d.), vehicle (DMSO) or no treatment, starting at day 2 after unilateral ureteric obstruction surgery and continuing until animals were killed on day 5. Cell proliferation was assessed by uptake of bromodeoxyuridine (BrdU). Results: In normal mice, phosphorylation (activation) of ERK (p-ERK) was restricted to collecting ducts. Western blotting identified a marked increase in p-ERK in the obstructed kidney in the no-treatment and vehicle-treated groups. Immunostaining showed strong p-ERK staining in many tubules and in interstitial cells. U0126 treatment inhibited ERK phosphorylation as assessed by western blot and immunostaining. The number of BrdU+ cortical tubular cells was reduced by vehicle treatment but was not further changed by U0126 treatment. In contrast, interstitial cell proliferation in the obstructed kidney was unaltered by vehicle treatment, but this was significantly inhibited by U0126. This was associated with a reduction in interstitial macrophage accumulation, but no effect was seen upon interstitial accumulation of α-SMA+ myofibroblasts. Renal fibrosis, as assessed by collagen deposition, was unaffected by U0126 or vehicle treatment. Conclusion: These studies show that accumulation of interstitial macrophages in the obstructed kidney is, in part, dependent upon the ERK signalling pathway.

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