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

Yamaguchi, Tomohiro; Pelling, Jill C.; Ramaswamy, Nadja T.; Eppler, Jason W.; Wallace, Darren P.; Nagao, Shizuko; Rome, L.; Sullivan, Lawrence P.; Grantham, Jared J.

doi:10.1046/j.1523-1755.2000.00991.x

Cited by 314 publications

(289 citation statements)

References 36 publications

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“…Also, the intracellular cAMP level has been reported to be increased in various models of PKD (20). Although cAMP inhibits the Raf-1/ERK pathway in normal epithelial cells, Yamaguchi et al (21,22) found that cAMP and adenylyl cyclase agonists stimulated the proliferation of cyst epithelial cells that were cultured from kidneys of patients with ADPKD by activating ERK via B-Raf. Furthermore, Chatterjee et al (23) reported that a glycosphingolipid lactosylceramide is upregulated in proximal tubular cells from human PKD kidneys and may stimulate cell proliferation via ERK.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

Omori¹,

Hida²,

Fujita³

et al. 2006

Journal of the American Society of Nephrology

132

104

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The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.

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Section: Discussionmentioning

confidence: 99%

“…Its mechanism of action is thought to be blockade of cAMP. ERK is the downstream target of cAMP in the cyst epithelium in PKD (20,21). Because targeting a downstream step generally is more efficient and more specific, inhibition of the ERK pathway may provide a promising approach to the treatment of PKD.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

Omori¹,

Hida²,

Fujita³

et al. 2006

Journal of the American Society of Nephrology

132

104

View full text Add to dashboard Cite

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“…These modifications of the ERK pathway are different from observations in cultured renal cells. Yamaguchi et al (44) showed that the cAMP-dependent proliferation of cultured human ADPKD cyst-lining cells is mediated through phosphorylation/activation of ERK. By contrast, cAMP inhibits ERK activity and slows proliferation in normal epithelial cells from human kidney cortex.…”

Section: Discussionmentioning

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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“…However, if we assume that the primary defect in type 2 ADPKD is PKD2-mediated Ca 2+ influx (and not Na + or K + which also pass through PKD2), it is possible that a connection between a Ca 2+ channel and cAMP can be made. It has been reported that cystic cells have abnormally high levels of cAMP [79][80][81][82] and the administration of a vasopressin V2 receptor antagonist, which reduced cAMP, suppressed the cystic phenotype in PKD2 knock out mice [83] and other animal models [84,85]. It is also known that store-operated Ca 2+ channels are directly coupled to specific isoforms of adenylyl cyclases [86][87][88].…”

Section: Pkd2-mediated Signal Transductionmentioning

confidence: 99%

Cell biology of polycystin-2

Tsiokas¹,

Kim²,

Ong³

2007

Cellular Signalling

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Naturally occurring mutations in two separate, but interacting loci, pkd1 and pkd2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common genetic diseases resulting primarily in the formation of large kidney, liver, and pancreatic cysts. Homozygous deletion of either pkd1 or pkd2 results in embryonic lethality in mice due to kidney and heart defects illustrating their indispensable roles in mammalian development. However, the mechanism by which mutations in these genes cause ADPKD and other developmental defects are unknown. Research in the past several years has revealed that PKD2 has multiple functions depending on its subcellular localization. It forms a receptor-operated, non-selective cation channel in the plasma membrane, a novel intracellular Ca 2+ release channel in the endoplasmic reticulum (ER), and a mechanosensitive channel in the primary cilium. This review focuses on the functional compartmentalization of PKD2, its modes of activation, and PKD2-mediated signal transduction.

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

Cited by 314 publications

References 36 publications

Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

Cell biology of polycystin-2

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