TY - JOUR
T1 - Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat
AU - Nagao, S.
AU - Nishii, K.
AU - Yoshihara, D.
AU - Kurahashi, H.
AU - Nagaoka, K.
AU - Yamashita, T.
AU - Takahashi, H.
AU - Yamaguchi, T.
AU - Calvet, J. P.
AU - Wallace, D. P.
N1 - Funding Information:
This work was supported by grants from the Japanese Ministry of Education Culture, Sports, Science and Technology ((High-Tech Research Center Project (2002), Open Research Center Project (2003), and 21st Century COE Program (2003)), the National Institutes of Health (P50 DK074043 (DPW and JPC)) and the PKD Foundation (DPW). We are grateful to Dr JJ Grantham for reading this paper and Mrs Ayumi Ohono for technical assistance.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.ki.5002629
DO - 10.1038/sj.ki.5002629
M3 - Article
C2 - 17943077
AN - SCOPUS:38149085428
SN - 0085-2538
VL - 73
SP - 269
EP - 277
JO - Kidney International
JF - Kidney International
IS - 3
ER -
