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- Title
cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway<sup>1</sup>.
- Authors
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.
- Abstract
cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. 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 (ERK1/2) 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...
- Subjects
POLYCYSTIC kidney disease; ADENOSINE monophosphate; EPIDERMAL growth factor
- Publication
Kidney International, 2000, Vol 57, Issue 4, p1460
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1046/j.1523-1755.2000.00991.x