Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat

Shizuko Nagao, K. Nishii, D. Yoshihara, Hiroki Kurahashi, K. Nagaoka, T. Yamashita, H. Takahashi, T. Yamaguchi, J. P. Calvet, D. P. Wallace

Research output: Contribution to journalArticle

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Abstract

In polycystic kidney disease, abnormal epithelial cell proliferation is the main factor leading to cyst formation and kidney enlargement. Cyclic AMP (cAMP) is mitogenic in cystic but antimitogenic in normal human kidney cells, which is due to reduced steady-state intracellular calcium levels in cystic compared to the normal cells. Inhibition of intracellular calcium entry with channel blockers, such as verapamil, induced cAMP-dependent cell proliferation in normal renal cells. To determine if calcium channel blockers have a similar effect on cell proliferation in vivo, Cy/+ rats, a model of dominant polycystic kidney disease, were treated with verapamil. Kidney weight and cyst index were elevated in verapamil-treated Cy/+ rats. This was associated with increased cell proliferation and apoptosis, elevated expression, and phosphorylation of B-Raf with stimulation of the mitogen-activated protein kinase MEK/ERK (mitogen-activated protein kinase kinase/extracellular-regulated kinase) pathway. Verapamil had no effect on kidney morphology or B-Raf stimulation in wild-type rats. We conclude that treatment of Cy/+ rats with calcium channel blockers increases activity of the B-Raf/MEK/ERK pathway accelerating cyst growth in the presence of endogenous cAMP, thus exacerbating renal cystic disease.

Original languageEnglish
Pages (from-to)269-277
Number of pages9
JournalKidney International
Volume73
Issue number3
DOIs
Publication statusPublished - 01-01-2008

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Polycystic Kidney Diseases
Calcium Channels
Disease Progression
Verapamil
Kidney
Cell Proliferation
Cyclic AMP
Cysts
Calcium Channel Blockers
Phosphotransferases
Cystic Kidney Diseases
Calcium
MAP Kinase Kinase Kinases
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Epithelial Cells
Phosphorylation
Apoptosis
Weights and Measures
Growth

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Nagao, Shizuko ; Nishii, K. ; Yoshihara, D. ; Kurahashi, Hiroki ; Nagaoka, K. ; Yamashita, T. ; Takahashi, H. ; Yamaguchi, T. ; Calvet, J. P. ; Wallace, D. P. / Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat. In: Kidney International. 2008 ; Vol. 73, No. 3. pp. 269-277.
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Nagao, S, Nishii, K, Yoshihara, D, Kurahashi, H, Nagaoka, K, Yamashita, T, Takahashi, H, Yamaguchi, T, Calvet, JP & Wallace, DP 2008, 'Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat', Kidney International, vol. 73, no. 3, pp. 269-277. https://doi.org/10.1038/sj.ki.5002629

Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat. / Nagao, Shizuko; Nishii, K.; Yoshihara, D.; Kurahashi, Hiroki; Nagaoka, K.; Yamashita, T.; Takahashi, H.; Yamaguchi, T.; Calvet, J. P.; Wallace, D. P.

In: Kidney International, Vol. 73, No. 3, 01.01.2008, p. 269-277.

Research output: Contribution to journalArticle

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