Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease

Shizuko Nagao, Tamio Yamaguchi, Masatomo Kusaka, Robin L. Maser, Hisahide Takahashi, Benjamin D. Cowley, Jared J. Grantham

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Abstract

Background. Abnormal proliferation of renal tubule epithelial cells is a central factor in the biogenesis and sustained expansion of cysts in autosomal-dominant polycystic kidney disease (ADPKD). Recent evidence from in vitro studies of human cyst wall epithelial cells has implicated a role for the mitogen-activated protein (MAP) kinase pathway in this aberrant proliferation. To determine the extent to which this signaling pathway is involved in cyst pathogenesis in vivo, we measured the expression of select components of the MAP kinase cascade in Han:SPRD rats with ADPKD at an early stage of the disease. Methods. Kidneys of 8-week-old normal Han:SPRD rats (+/+) or rats heterozygous (Cy/+) for ADPKD were examined by Western blot analysis and immunohistochemistry to determine the expression of extracellular-regulated kinase (ERK), phosphorylated ERK (P-ERK), Raf-1 (MAPKKK), phosphorylated Raf-1 (P-Raf-1), B-Raf, Rap-1 and phosphorylated protein kinase A (P-PKA). Results. P-ERK was expressed to a greater extent in Cy/+ kidneys (3.74 ± 1.07 fold) than in normal kidneys, whereas ERK abundance was not different. P-Raf-1 levels were higher in Cy/+ than in +/+ kidneys (1.53 ± 0.08 fold) consistent with upstream stimulation of receptor tyrosine kinase. B-Raf and Raf-1 abundances were greater in Cy/+ than in +/+ (1.74 ± 0.25 and 1.27 ± 0.08 fold, respectively). In Cy/+, immunohistochemistry showed increased P-ERK and B-Raf expression in the abnormal mural epithelial cells within cysts. These findings, together with the detection of P-PKA and the small G protein, Rap-1, in cyst epithelial cells, implicate a potential role for cyclic adenosine monophosphate (AMP) in the activation of ERK in ADPKD cells. Conclusions. We conclude that the MAP kinase pathway is activated to the level of ERK in the abnormal mural epithelial cells lining cysts in animals with a dominantly inherited type of polycystic kidney disease. We suggest that cAMP, acting through PKA, Rap-1 and B-Raf, may contribute to the activation of ERK in a way that complements receptor tyrosine kinase-mediated agonists in the promotion of cyst enlargement.

Original languageEnglish
Pages (from-to)427-437
Number of pages11
JournalKidney International
Volume63
Issue number2
DOIs
Publication statusPublished - 01-01-2003

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Autosomal Dominant Polycystic Kidney
Extracellular Signal-Regulated MAP Kinases
Cysts
Kidney
Phosphotransferases
Epithelial Cells
Mitogen-Activated Protein Kinases
Cyclic AMP-Dependent Protein Kinases
Immunohistochemistry
Proto-Oncogene Proteins c-raf
MAP Kinase Kinase Kinases
Complement Receptors
Polycystic Kidney Diseases
Monomeric GTP-Binding Proteins
Receptor Protein-Tyrosine Kinases
Cyclic AMP
Protein-Tyrosine Kinases
Western Blotting

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Nagao, Shizuko ; Yamaguchi, Tamio ; Kusaka, Masatomo ; Maser, Robin L. ; Takahashi, Hisahide ; Cowley, Benjamin D. ; Grantham, Jared J. / Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease. In: Kidney International. 2003 ; Vol. 63, No. 2. pp. 427-437.
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abstract = "Background. Abnormal proliferation of renal tubule epithelial cells is a central factor in the biogenesis and sustained expansion of cysts in autosomal-dominant polycystic kidney disease (ADPKD). Recent evidence from in vitro studies of human cyst wall epithelial cells has implicated a role for the mitogen-activated protein (MAP) kinase pathway in this aberrant proliferation. To determine the extent to which this signaling pathway is involved in cyst pathogenesis in vivo, we measured the expression of select components of the MAP kinase cascade in Han:SPRD rats with ADPKD at an early stage of the disease. Methods. Kidneys of 8-week-old normal Han:SPRD rats (+/+) or rats heterozygous (Cy/+) for ADPKD were examined by Western blot analysis and immunohistochemistry to determine the expression of extracellular-regulated kinase (ERK), phosphorylated ERK (P-ERK), Raf-1 (MAPKKK), phosphorylated Raf-1 (P-Raf-1), B-Raf, Rap-1 and phosphorylated protein kinase A (P-PKA). Results. P-ERK was expressed to a greater extent in Cy/+ kidneys (3.74 ± 1.07 fold) than in normal kidneys, whereas ERK abundance was not different. P-Raf-1 levels were higher in Cy/+ than in +/+ kidneys (1.53 ± 0.08 fold) consistent with upstream stimulation of receptor tyrosine kinase. B-Raf and Raf-1 abundances were greater in Cy/+ than in +/+ (1.74 ± 0.25 and 1.27 ± 0.08 fold, respectively). In Cy/+, immunohistochemistry showed increased P-ERK and B-Raf expression in the abnormal mural epithelial cells within cysts. These findings, together with the detection of P-PKA and the small G protein, Rap-1, in cyst epithelial cells, implicate a potential role for cyclic adenosine monophosphate (AMP) in the activation of ERK in ADPKD cells. Conclusions. We conclude that the MAP kinase pathway is activated to the level of ERK in the abnormal mural epithelial cells lining cysts in animals with a dominantly inherited type of polycystic kidney disease. We suggest that cAMP, acting through PKA, Rap-1 and B-Raf, may contribute to the activation of ERK in a way that complements receptor tyrosine kinase-mediated agonists in the promotion of cyst enlargement.",
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Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease. / Nagao, Shizuko; Yamaguchi, Tamio; Kusaka, Masatomo; Maser, Robin L.; Takahashi, Hisahide; Cowley, Benjamin D.; Grantham, Jared J.

In: Kidney International, Vol. 63, No. 2, 01.01.2003, p. 427-437.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease

AU - Nagao, Shizuko

AU - Yamaguchi, Tamio

AU - Kusaka, Masatomo

AU - Maser, Robin L.

AU - Takahashi, Hisahide

AU - Cowley, Benjamin D.

AU - Grantham, Jared J.

PY - 2003/1/1

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N2 - Background. Abnormal proliferation of renal tubule epithelial cells is a central factor in the biogenesis and sustained expansion of cysts in autosomal-dominant polycystic kidney disease (ADPKD). Recent evidence from in vitro studies of human cyst wall epithelial cells has implicated a role for the mitogen-activated protein (MAP) kinase pathway in this aberrant proliferation. To determine the extent to which this signaling pathway is involved in cyst pathogenesis in vivo, we measured the expression of select components of the MAP kinase cascade in Han:SPRD rats with ADPKD at an early stage of the disease. Methods. Kidneys of 8-week-old normal Han:SPRD rats (+/+) or rats heterozygous (Cy/+) for ADPKD were examined by Western blot analysis and immunohistochemistry to determine the expression of extracellular-regulated kinase (ERK), phosphorylated ERK (P-ERK), Raf-1 (MAPKKK), phosphorylated Raf-1 (P-Raf-1), B-Raf, Rap-1 and phosphorylated protein kinase A (P-PKA). Results. P-ERK was expressed to a greater extent in Cy/+ kidneys (3.74 ± 1.07 fold) than in normal kidneys, whereas ERK abundance was not different. P-Raf-1 levels were higher in Cy/+ than in +/+ kidneys (1.53 ± 0.08 fold) consistent with upstream stimulation of receptor tyrosine kinase. B-Raf and Raf-1 abundances were greater in Cy/+ than in +/+ (1.74 ± 0.25 and 1.27 ± 0.08 fold, respectively). In Cy/+, immunohistochemistry showed increased P-ERK and B-Raf expression in the abnormal mural epithelial cells within cysts. These findings, together with the detection of P-PKA and the small G protein, Rap-1, in cyst epithelial cells, implicate a potential role for cyclic adenosine monophosphate (AMP) in the activation of ERK in ADPKD cells. Conclusions. We conclude that the MAP kinase pathway is activated to the level of ERK in the abnormal mural epithelial cells lining cysts in animals with a dominantly inherited type of polycystic kidney disease. We suggest that cAMP, acting through PKA, Rap-1 and B-Raf, may contribute to the activation of ERK in a way that complements receptor tyrosine kinase-mediated agonists in the promotion of cyst enlargement.

AB - Background. Abnormal proliferation of renal tubule epithelial cells is a central factor in the biogenesis and sustained expansion of cysts in autosomal-dominant polycystic kidney disease (ADPKD). Recent evidence from in vitro studies of human cyst wall epithelial cells has implicated a role for the mitogen-activated protein (MAP) kinase pathway in this aberrant proliferation. To determine the extent to which this signaling pathway is involved in cyst pathogenesis in vivo, we measured the expression of select components of the MAP kinase cascade in Han:SPRD rats with ADPKD at an early stage of the disease. Methods. Kidneys of 8-week-old normal Han:SPRD rats (+/+) or rats heterozygous (Cy/+) for ADPKD were examined by Western blot analysis and immunohistochemistry to determine the expression of extracellular-regulated kinase (ERK), phosphorylated ERK (P-ERK), Raf-1 (MAPKKK), phosphorylated Raf-1 (P-Raf-1), B-Raf, Rap-1 and phosphorylated protein kinase A (P-PKA). Results. P-ERK was expressed to a greater extent in Cy/+ kidneys (3.74 ± 1.07 fold) than in normal kidneys, whereas ERK abundance was not different. P-Raf-1 levels were higher in Cy/+ than in +/+ kidneys (1.53 ± 0.08 fold) consistent with upstream stimulation of receptor tyrosine kinase. B-Raf and Raf-1 abundances were greater in Cy/+ than in +/+ (1.74 ± 0.25 and 1.27 ± 0.08 fold, respectively). In Cy/+, immunohistochemistry showed increased P-ERK and B-Raf expression in the abnormal mural epithelial cells within cysts. These findings, together with the detection of P-PKA and the small G protein, Rap-1, in cyst epithelial cells, implicate a potential role for cyclic adenosine monophosphate (AMP) in the activation of ERK in ADPKD cells. Conclusions. We conclude that the MAP kinase pathway is activated to the level of ERK in the abnormal mural epithelial cells lining cysts in animals with a dominantly inherited type of polycystic kidney disease. We suggest that cAMP, acting through PKA, Rap-1 and B-Raf, may contribute to the activation of ERK in a way that complements receptor tyrosine kinase-mediated agonists in the promotion of cyst enlargement.

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