Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells.
BACKGROUND
Progressive cyst enlargement, the hallmark of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-recessive (ARPKD) polycystic kidney disease, precedes the eventual decline of function in these conditions. The expansion of individual cysts in ADPKD is determined to a major extent by mural epithelial cell proliferation and transepithelial fluid secretion. This study determined if common receptor-mediated agonists and an anonymous lipid stimulate the production of 3' 5'-cyclic monophosphate (cAMP) in mural epithelial cells from the two major types of human cystic diseases.


METHODS
cAMP responses to maximally effective concentrations of renal agonists were determined together with measurements of transepithelial anion current and cellular proliferation and extracellular signal-related kinase (ERK 1/2) expression in primary cultures of epithelial cells from human ADPKD and ARPKD cysts.


RESULTS
The rank orders of responses to ligands for ADPKD and ARPKD cells were identical: epinephrine > desmopressin (DDAVP) approximately arginine vasopressin (AVP) > adenosine > prostaglandin E(2) (PGE(2)) > parathyroid hormone (PTH). cAMP concentrations elevated by epinephrine, DDAVP, adenosine, and PGE(2) were diminished by receptor-specific inhibitors. Pools of cyst fluid collected individually from 16 of 19 ADPKD kidneys increased, to varying degrees, cAMP levels in ADPKD and ARPKD cells. PGE(2), beta-adrenergic and AVP antagonists partially inhibited cAMP accumulation in response to fluids from three kidneys, but a large portion of the endogenous activity was attributed to yet-to-be identified bioactive lipid, designated cyst activating factor (CAF). CAF stimulated cAMP production in ADPKD and ARPKD cells, activated ERK(1/2), and increased cellular proliferation in ADPKD cells. CAF increased positive short circuit current (I(SC)) in polarized ADPKD and T-84 monolayers, indicating stimulation of net anion secretion.


CONCLUSIONS
Endogenous adenylyl cyclase agonists promote cell proliferation and electrolyte secretion of human ADPKD and ARPKD cells in vitro. We suggest that increased levels of cAMP may accelerate cyst growth and overall renal enlargement in patients with PKD.
Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas 66160-7382, USA.
Franck A
FA
Belibi
Gail
G
Reif
Darren P
DP
Wallace
Tamio
T
Yamaguchi
Lincoln
L
Olsen
Hong
H
Li
George M
GM
Helmkamp
Jared J
JJ
Grantham
D000322:Adrenergic Agonists / Q000494:pharmacology; D000328:Adult; D001127:Arginine Vasopressin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism*; D020420:Cyst Fluid / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000494:pharmacology; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism* / Q000473:pathology; D012076:Renal Agents / Q000494:pharmacology
D000322:Adrenergic Agonists; D010281:Parathyroid Hormone; D012076:Renal Agents; D001127:Arginine Vasopressin; D000242:Cyclic AMP; D003894:Deamino Arginine Vasopressin; D015232:Dinoprostone; D004837:Epinephrine