Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat.
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.
Nagao
S
S
Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Toyoake, Aichi, Japan.
Nishii
K
K
Yoshihara
D
D
Kurahashi
H
H
Nagaoka
K
K
Yamashita
T
T
Takahashi
H
H
Yamaguchi
T
T
Calvet
J P
JP
Wallace
D P
DP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D003560:Cysts / Q000139:chemically induced; D018450:Disease Progression; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D007690:Polycystic Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000009:adverse effects*
D002121:Calcium Channel Blockers; D014700:Verapamil; D000242:Cyclic AMP; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D002118:Calcium