Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease

Nagao, Shizuko; Yamaguchi, Tomohiro; Kusaka, Masaru; Maser, Robin L.; Takahashi, Hisahide; Cowley, Benjamin D.; Grantham, Jared J.

doi:10.1046/j.1523-1755.2003.00755.x

Cited by 95 publications

(97 citation statements)

References 37 publications

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“…Several studies have linked MAPK signaling to cyst formation. Upregulation of ERK has been reported previously in the Han:SPRD rat model for ADPKD and the bcl-2 Ϫ/Ϫ mouse model for cystic kidney disease (27,28). Increased activity of JNK was reported recently in small cysts in another mouse model for polycystic kidney disease (29).…”

Section: Discussionmentioning

confidence: 74%

Increased Activity of Activator Protein-1 Transcription Factor Components ATF2, c-Jun, and c-Fos in Human and Mouse Autosomal Dominant Polycystic Kidney Disease

Wal²,

Bent³

et al. 2005

Journal of the American Society of Nephrology

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Autosomal dominant polycystic kidney disease is a common inherited disorder that predominantly manifests with the formation of fluid-filled cysts in both kidneys. The disease can be accounted for by a mutation in either the PKD1 or the PKD2 gene. It was demonstrated previously that aberrant expression of the PKD1 gene product, polycystin-1, results in modification of activator protein-1 (AP-1) transcription factor activity in cultured renal epithelial cells. Here, it is reported that activity of the AP-1 components c-Jun, ATF2, and c-Fos is altered in renal cystic tissue of patients with autosomal dominant polycystic kidney disease and of hypomorphic Pkd1 mice with polycystic kidney disease. Data were obtained using immunohistochemical and Western blot analysis. Significant upregulation of Thr71-and Thr69/71-phosphorylated ATF2 and Ser73-phosphorylated c-Jun and increased c-Fos were detected in small cysts and (dilated) ducts and tubules surrounded by fibrotic interstitium. The data indicate that various AP-1 components are constitutively activated in polycystic kidney disease and suggest that aberrant AP-1 activity is relevant for cyst formation.

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Section: Discussionmentioning

confidence: 74%

Increased Activity of Activator Protein-1 Transcription Factor Components ATF2, c-Jun, and c-Fos in Human and Mouse Autosomal Dominant Polycystic Kidney Disease

Wal²,

Bent³

et al. 2005

Journal of the American Society of Nephrology

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“…Nagao et al (19) reported increased expression of P-ERK in the cyst epithelium of Han:SPRD rats, a model of autosomal dominant PKD (ADPKD). Increased ERK activity in cyst epithelium therefore may be a common feature of cystic diseases.…”

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

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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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“…The functional significance of these observations is profound. In the kidney, ERK1/2 is expressed in all nephron segments and plays an important role in multiple physiological (33) and pathological processes (30). In contrast to other nephron segments, ERK1/2 appears to have basal activity in distal nephron cells (31,34), consistent with tonic inhibition of Na ϩ transport by the ERK pathway.…”

Section: Gilz1 and Sgk1 Synergistically Stimulate Enac Cell Surface Ementioning

confidence: 97%

“…4). This association of PI3K and Raf-1 pathway components into an ion transport regulatory complex provides a novel mechanism for achieving signaling specificity (9,10,(28)(29)(30)(31). Through this mechanism, ion transport can be selectively stimulated while having little or no effect on context-inappropriate targets.…”

Section: Gilz1 and Sgk1 Synergistically Stimulate Enac Cell Surface Ementioning

confidence: 99%

Epithelial sodium channel regulated by differential composition of a signaling complex

Soundararajan¹,

Melters²,

Shih³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Hormonal control of transepithelial sodium (Na ؉ ) transport utilizes phosphatidylinositide 3 -kinase (PI3K) and Raf-MAPK/ERK kinase (MEK)-ERK-dependent signaling pathways, which impact numerous cell functions. How signals transmitted by these pathways are sorted and appropriately transmitted to alter Na ؉ transport without altering other physiologic processes is not well understood. Here, we report the identification of a signaling complex that selectively modulates the cell surface expression of the epithelial sodium channel (ENaC), an ion channel that is essential for fluid and electrolyte balance in mammals. Raf-1 and the ubiquitin ligase, Nedd4-2, are constitutively-expressed inhibitory components of this ENaC regulatory complex, which interact with, and decrease the expression of, cell surface ENaC. The activities of Nedd4-2 and Raf-1 are inhibited cooperatively by the PI3K-dependent kinase serum-and glucocorticoid-induced kinase 1 (SGK1), and the Raf-1-interacting protein glucocorticoid-induced leucine zipper (GILZ1), which are aldosterone-stimulated components of the complex. Together, SGK1 and GILZ1 synergistically stimulate ENaC cell surface expression. Interestingly, GILZ1 and SGK1 do not have synergistic, and in fact have opposite, effects on an unrelated activity, FKHRL1-driven gene transcription. Together, these data suggest that GILZ1 and SGK1 provide a physical and functional link between the PI3K-and Raf-1-dependent signaling modules and represent a unique mechanism for specifically controlling Na ؉ transport without inappropriately activating other cell functions.glucocorticoid-induced leucine zipper protein ͉ Nedd4-2 ͉ Raf-1 ͉ serum-and glucocorticoid-induced kinase 1

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Renal activation of extracellular signal-regulated kinase in rats with autosomal-dominant polycystic kidney disease

Cited by 95 publications

References 37 publications

Increased Activity of Activator Protein-1 Transcription Factor Components ATF2, c-Jun, and c-Fos in Human and Mouse Autosomal Dominant Polycystic Kidney Disease

Increased Activity of Activator Protein-1 Transcription Factor Components ATF2, c-Jun, and c-Fos in Human and Mouse Autosomal Dominant Polycystic Kidney Disease

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

Epithelial sodium channel regulated by differential composition of a signaling complex

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