cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway

Tamio Yamaguchi, Jill C. Pelling, Nadja T. Ramaswamy, Jason W. Eppler, Darren P. Wallace, Shizuko Nagao, Lorraine A. Rome, Lawrence P. Sullivan, Jared J. Grantham

研究成果: Article

234 引用 (Scopus)

抄録

Background. Cellular proliferation is a key factor in the enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in vitro proliferation of cyst epithelial cells derived from human ADPKD cysts. Methods. Epithelial cells from cysts of individuals with ADPKD and from normal human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects of agonists and inhibitors on the rate of cellular proliferation and the activation of extracellular signal-regulated kinase (ERK(1/2)) were determined. Results. 8-Br-cAMP (100 μmol/L) stimulated the proliferation of cells from eight different ADPKD subjects to 99.0% above baseline; proliferation was inhibited by protein kinase A (PKA) antagonists H-89 (97%) and Rp-cAMP (90%). Forskolin (10 μmol/L), which activates adenylyl cyclase, increased proliferation 124%, and receptor-mediated agonists arginine vasopressin, desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2 stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3%, respectively. The mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD cell proliferation in response to cAMP agonists, but genistein, a receptor tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP agonists increased the activity of ERK above control levels within five minutes. In contrast to ADPKD, proliferation and ERK activity of cells derived from normal HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was increased by these agonists in both ADPKD and HKC cell monolayers. Conclusions. We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC epithelial cells through PKA activation of the ERK pathway at a locus distal to receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway may have a unique role in determining the rate of cyst enlargement in ADPKD through in actions to stimulate cellular proliferation and transepithelial solute and fluid secretion.

元の言語English
ページ(範囲)1460-1471
ページ数12
ジャーナルKidney International
57
発行部数4
DOI
出版物ステータスPublished - 01-01-2000
外部発表Yes

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Autosomal Dominant Polycystic Kidney
Extracellular Signal-Regulated MAP Kinases
Cysts
Epithelial Cells
Kidney
Kidney Cortex
Cell Proliferation
Receptor Protein-Tyrosine Kinases
Cyclic AMP-Dependent Protein Kinases
Adenylyl Cyclases
In Vitro Techniques
Fluids and Secretions
Deamino Arginine Vasopressin
Secretin
Mitogen-Activated Protein Kinase 3
MAP Kinase Signaling System
Arginine Vasopressin
Genistein
Vasoactive Intestinal Peptide
Colforsin

All Science Journal Classification (ASJC) codes

  • Nephrology

これを引用

Yamaguchi, Tamio ; Pelling, Jill C. ; Ramaswamy, Nadja T. ; Eppler, Jason W. ; Wallace, Darren P. ; Nagao, Shizuko ; Rome, Lorraine A. ; Sullivan, Lawrence P. ; Grantham, Jared J. / cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. :: Kidney International. 2000 ; 巻 57, 番号 4. pp. 1460-1471.
@article{b42a46e2e34349f4adb047154fb0516f,
title = "cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway",
abstract = "Background. Cellular proliferation is a key factor in the enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in vitro proliferation of cyst epithelial cells derived from human ADPKD cysts. Methods. Epithelial cells from cysts of individuals with ADPKD and from normal human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects of agonists and inhibitors on the rate of cellular proliferation and the activation of extracellular signal-regulated kinase (ERK(1/2)) were determined. Results. 8-Br-cAMP (100 μmol/L) stimulated the proliferation of cells from eight different ADPKD subjects to 99.0{\%} above baseline; proliferation was inhibited by protein kinase A (PKA) antagonists H-89 (97{\%}) and Rp-cAMP (90{\%}). Forskolin (10 μmol/L), which activates adenylyl cyclase, increased proliferation 124{\%}, and receptor-mediated agonists arginine vasopressin, desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2 stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3{\%}, respectively. The mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD cell proliferation in response to cAMP agonists, but genistein, a receptor tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP agonists increased the activity of ERK above control levels within five minutes. In contrast to ADPKD, proliferation and ERK activity of cells derived from normal HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was increased by these agonists in both ADPKD and HKC cell monolayers. Conclusions. We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC epithelial cells through PKA activation of the ERK pathway at a locus distal to receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway may have a unique role in determining the rate of cyst enlargement in ADPKD through in actions to stimulate cellular proliferation and transepithelial solute and fluid secretion.",
author = "Tamio Yamaguchi and Pelling, {Jill C.} and Ramaswamy, {Nadja T.} and Eppler, {Jason W.} and Wallace, {Darren P.} and Shizuko Nagao and Rome, {Lorraine A.} and Sullivan, {Lawrence P.} and Grantham, {Jared J.}",
year = "2000",
month = "1",
day = "1",
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Yamaguchi, T, Pelling, JC, Ramaswamy, NT, Eppler, JW, Wallace, DP, Nagao, S, Rome, LA, Sullivan, LP & Grantham, JJ 2000, 'cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway', Kidney International, 巻. 57, 番号 4, pp. 1460-1471. https://doi.org/10.1046/j.1523-1755.2000.00991.x

cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. / Yamaguchi, Tamio; Pelling, Jill C.; Ramaswamy, Nadja T.; Eppler, Jason W.; Wallace, Darren P.; Nagao, Shizuko; Rome, Lorraine A.; Sullivan, Lawrence P.; Grantham, Jared J.

:: Kidney International, 巻 57, 番号 4, 01.01.2000, p. 1460-1471.

研究成果: Article

TY - JOUR

T1 - cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway

AU - Yamaguchi, Tamio

AU - Pelling, Jill C.

AU - Ramaswamy, Nadja T.

AU - Eppler, Jason W.

AU - Wallace, Darren P.

AU - Nagao, Shizuko

AU - Rome, Lorraine A.

AU - Sullivan, Lawrence P.

AU - Grantham, Jared J.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - Background. Cellular proliferation is a key factor in the enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in vitro proliferation of cyst epithelial cells derived from human ADPKD cysts. Methods. Epithelial cells from cysts of individuals with ADPKD and from normal human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects of agonists and inhibitors on the rate of cellular proliferation and the activation of extracellular signal-regulated kinase (ERK(1/2)) were determined. Results. 8-Br-cAMP (100 μmol/L) stimulated the proliferation of cells from eight different ADPKD subjects to 99.0% above baseline; proliferation was inhibited by protein kinase A (PKA) antagonists H-89 (97%) and Rp-cAMP (90%). Forskolin (10 μmol/L), which activates adenylyl cyclase, increased proliferation 124%, and receptor-mediated agonists arginine vasopressin, desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2 stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3%, respectively. The mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD cell proliferation in response to cAMP agonists, but genistein, a receptor tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP agonists increased the activity of ERK above control levels within five minutes. In contrast to ADPKD, proliferation and ERK activity of cells derived from normal HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was increased by these agonists in both ADPKD and HKC cell monolayers. Conclusions. We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC epithelial cells through PKA activation of the ERK pathway at a locus distal to receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway may have a unique role in determining the rate of cyst enlargement in ADPKD through in actions to stimulate cellular proliferation and transepithelial solute and fluid secretion.

AB - Background. Cellular proliferation is a key factor in the enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in vitro proliferation of cyst epithelial cells derived from human ADPKD cysts. Methods. Epithelial cells from cysts of individuals with ADPKD and from normal human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects of agonists and inhibitors on the rate of cellular proliferation and the activation of extracellular signal-regulated kinase (ERK(1/2)) were determined. Results. 8-Br-cAMP (100 μmol/L) stimulated the proliferation of cells from eight different ADPKD subjects to 99.0% above baseline; proliferation was inhibited by protein kinase A (PKA) antagonists H-89 (97%) and Rp-cAMP (90%). Forskolin (10 μmol/L), which activates adenylyl cyclase, increased proliferation 124%, and receptor-mediated agonists arginine vasopressin, desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2 stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3%, respectively. The mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD cell proliferation in response to cAMP agonists, but genistein, a receptor tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP agonists increased the activity of ERK above control levels within five minutes. In contrast to ADPKD, proliferation and ERK activity of cells derived from normal HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was increased by these agonists in both ADPKD and HKC cell monolayers. Conclusions. We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC epithelial cells through PKA activation of the ERK pathway at a locus distal to receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway may have a unique role in determining the rate of cyst enlargement in ADPKD through in actions to stimulate cellular proliferation and transepithelial solute and fluid secretion.

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