Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells

Belibi, Franck A.; Reif, Gail A.; Wallace, Darren P.; Yamaguchi, Tomohiro; Olsen, Lincoln T.; Li, Hong; Helmkamp, George M.; Grantham, Jared J.

doi:10.1111/j.1523-1755.2004.00843.x

Cited by 246 publications

(224 citation statements)

References 39 publications

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“…For example, EGF and TGF-␣ elicit mitogenic effect in ADPKD cells by the MEK-ERK pathway through binding to receptor tyrosine kinase (21)(22)(23)(24), and cAMP promotes growth and secretion of ADPKD cells via B-Raf/MEK/ERK (21,43). Our results show that ouabain caused phosphorylation of ERK in ADPKD cells within 15 min of addition of the steroid, ERK phosphorylation was maximal at nanomolar ouabain concentrations, and inhibition of MEK blocked the effect.…”

Section: Discussionmentioning

confidence: 53%

“…Therefore, under physiologic conditions, endogenous ouabain can readily activate the MEK-ERK pathway in the cyst cells of ADPKD kidneys, representing a factor that may have a direct impact on the growth of the cysts. A variety of circulating factors, hormones, and autocoids have been shown to stimulate the proliferation of renal cyst epithelial cells (21,27,(23)(24)(25)48,49). This study is the first to demonstrate that ouabain, an endogenous steroid hormone, has a positive effect on proliferation of ADPKD cells.…”

Section: Discussionmentioning

confidence: 72%

“…However, the progressive enlargement of cysts seems to be regulated by a variety of factors, including growth hormones and cAMP agonists (18 -20). Arginine vasopressin (AVP) and EGF stimulate cell proliferation of human ADPKD cells through activation of the MEK-ERK pathway (21)(22)(23)(24). cAMP causes cell proliferation in human cells and animal models of PKD, also via the MEK-ERK pathway, through B-Raf, a kinase that phosphorylates and activates MEK (25,26).…”

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confidence: 99%

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Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Nguyen¹,

Wallace²,

Blanco³

2007

Journal of the American Society of Nephrology

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108

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In autosomal dominant polycystic kidney disease (ADPKD), cyst formation and enlargement require proliferation of mural renal epithelial cells and the transepithelial secretion of fluid into the cyst cavity. Na,K-ATPase is essential for solute and water transport in ADPKD cells, and ouabain blocks fluid secretion in these cells. By binding to the Na,K-ATPase, ouabain also induces proliferation in some cell types. Surprisingly, it was found that nanomolar concentrations of ouabain, similar to those circulating in blood, induced ADPKD cell proliferation but had no statistically significant effect on normal human kidney (NHK) cells. Ouabain, acting from the basolateral side of the cells, also caused an increase in the level of phosphorylated extracellular signal-regulated kinases (ERK). Mitogen-activated protein kinase kinase (MEK) inhibitor U0126 blocked ouabain-induced ERK activation and cell proliferation, suggesting that ouabain effect is mediated through the MEK-ERK pathway. In contrast to NHK cells, the dose-response curve for ouabain inhibition of Na,K-ATPase activity indicated that approximately 20% of the enzyme in ADPKD cells exhibits a higher affinity for ouabain. The increased ouabain affinity of ADPKD cells was not due to differences in Na,K-ATPase isoform expression because these cells, like NHK cells, possess only the ␣1 and ␤1 subunits. The ␥ variants of the Na,K-ATPase also are expressed in the cells but are elevated in ADPKD cells. Currently, the basis for the differences in ouabain sensitivity of NHK and ADPKD cells is unknown. It is concluded that ouabain stimulates proliferation in ADPKD cells by binding to the Na,K-ATPase with high affinity and via activation of the MEK-ERK pathway.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

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Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Nguyen¹,

Wallace²,

Blanco³

2007

Journal of the American Society of Nephrology

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108

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“…Experimental studies have implicated a central role for cAMP in promoting cyst growth (6). cAMP stimulates cyst formation by promoting chloride-driven fluid secretion and by stimulating activation and proliferation of cyst-derived cells (7). In line with this potential detrimental role of VP are the findings in animal models of polycystic kidney disease, in which blocking the effect of VP (and consequently decreasing cAMP levels) by a pharmacologic agent (8)(9)(10) or by drinking more water (11) led to reduction of cyst formation and renal function preservation.…”

Section: Introductionmentioning

confidence: 99%

Copeptin, a Surrogate Marker of Vasopressin, Is Associated with Disease Severity in Autosomal Dominant Polycystic Kidney Disease

Meijer¹,

Bakker²,

Jagt³

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Experimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD.Design, setting, participants, & measurements Plasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay. Plasma and urinary osmolarity were also measured. To assess disease severity, GFR and effective renal blood flow were measured by continuous infusion of 125 I-iothalamate and 131 I-hippuran, total renal volume by magnetic resonance imaging, and 24-hour urinary albumin excretion by nephelometry. ResultsIn these ADPKD patients, copeptin was associated with the various markers of disease severity in ADPKD (positively with total renal volume [R ϭ 0.47] and albuminuria [R ϭ 0.39] and negatively with GFR [R ϭ Ϫ0.58] and effective renal blood flow [R ϭ Ϫ0.52], all P Ͻ 0.001). These associations were independent of age, gender, and use of diuretics. Copeptin was furthermore associated with plasma osmolarity (P Ͻ 0.001) but not with 24-hour urinary volume, 24-hour urinary osmolarity or fractional urea excretion (P ϭ 0.7, 0.9, and 0.3, respectively). ConclusionsOn cross-sectional analysis, copeptin is associated with disease severity in ADPKD patients, supporting the results of experimental studies that suggest that vasopressin antagonists have a renoprotective effect in ADPKD and offering a good prospect for clinical studies with these agents.

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“…Exposure to cAMP agonists stimulates fluid secretion across monolayers of ADPKD cyst-lining epithelial cells (6), as well as the proliferation of these cells (7). Furthermore, increased levels of cAMP resulting from the activation of vasopressin (AVP) V2 receptor (V2R) pathway in CD cells may contribute to the progression of cystogenesis.…”

mentioning

confidence: 99%

PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

Ahrabi¹,

Terryn²,

Valenti³

et al. 2007

Journal of the American Society of Nephrology

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Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells

Abstract: 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.

Cited by 246 publications

References 39 publications

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal–Regulated Kinase Activation and Cell Proliferation

Copeptin, a Surrogate Marker of Vasopressin, Is Associated with Disease Severity in Autosomal Dominant Polycystic Kidney Disease

PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

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