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 cyst...
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| Veröffentlicht in: | Kidney international 2008-02, Vol.73 (3), p.269-277 |
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| creator | Nagao, S. Nishii, K. Yoshihara, D. Kurahashi, H. Nagaoka, K. Yamashita, T. Takahashi, H. Yamaguchi, T. Calvet, J.P. Wallace, D.P. |
| description | 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. |
| doi_str_mv | 10.1038/sj.ki.5002629 |
| format | Article |
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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.</description><identifier>ISSN: 0085-2538</identifier><identifier>EISSN: 1523-1755</identifier><identifier>DOI: 10.1038/sj.ki.5002629</identifier><identifier>PMID: 17943077</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ADPKD ; Animals ; Apoptosis - drug effects ; Blood Urea Nitrogen ; calcium ; Calcium - metabolism ; Calcium Channel Blockers - adverse effects ; Cell Proliferation - drug effects ; cell signaling ; cyclic AMP ; Cyclic AMP - metabolism ; Cysts - chemically induced ; Disease Progression ; Female ; Kidney - drug effects ; Kidney - metabolism ; Kidney - pathology ; Male ; MAP Kinase Signaling System - drug effects ; Organ Size - drug effects ; Polycystic Kidney Diseases - chemically induced ; Polycystic Kidney Diseases - metabolism ; Polycystic Kidney Diseases - pathology ; proliferation ; Proto-Oncogene Proteins B-raf - metabolism ; Rats ; Rats, Sprague-Dawley ; Verapamil - adverse effects</subject><ispartof>Kidney international, 2008-02, Vol.73 (3), p.269-277</ispartof><rights>2008 International Society of Nephrology</rights><rights>Copyright Nature Publishing Group Feb 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c437t-213cafc7681d94411f0ba4a9054976cd052b63b4afa6987f54a4ad876f269d203</citedby><cites>FETCH-LOGICAL-c437t-213cafc7681d94411f0ba4a9054976cd052b63b4afa6987f54a4ad876f269d203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17943077$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nagao, S.</creatorcontrib><creatorcontrib>Nishii, K.</creatorcontrib><creatorcontrib>Yoshihara, D.</creatorcontrib><creatorcontrib>Kurahashi, H.</creatorcontrib><creatorcontrib>Nagaoka, K.</creatorcontrib><creatorcontrib>Yamashita, T.</creatorcontrib><creatorcontrib>Takahashi, H.</creatorcontrib><creatorcontrib>Yamaguchi, T.</creatorcontrib><creatorcontrib>Calvet, J.P.</creatorcontrib><creatorcontrib>Wallace, D.P.</creatorcontrib><title>Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat</title><title>Kidney international</title><addtitle>Kidney Int</addtitle><description>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.</description><subject>ADPKD</subject><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Blood Urea Nitrogen</subject><subject>calcium</subject><subject>Calcium - metabolism</subject><subject>Calcium Channel Blockers - adverse effects</subject><subject>Cell Proliferation - drug effects</subject><subject>cell signaling</subject><subject>cyclic AMP</subject><subject>Cyclic AMP - metabolism</subject><subject>Cysts - chemically induced</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Organ Size - drug effects</subject><subject>Polycystic Kidney Diseases - chemically induced</subject><subject>Polycystic Kidney Diseases - metabolism</subject><subject>Polycystic Kidney Diseases - pathology</subject><subject>proliferation</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Verapamil - adverse effects</subject><issn>0085-2538</issn><issn>1523-1755</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kE1r3DAQhkVIabZpj7kGkUsOxRt9WJZ1LEv6AYFe2ltByNI4q12vvNXYAf_7KuxCodDTMMwzLy8PITecrTmT7QPu1vu4VoyJRpgLsuJKyIprpS7JirFWVULJ9oq8Q9yxshvJ3pIrrk0tmdYr8mvjBh_nA_VblxIMNKZt7OIUx0Sd9zBAdhMgPY7D4hecoqf7GBIsNEQEh0CPeXzOgPj6EROdtkA3y8NHWv7ekze9GxA-nOc1-fn58cfma_X0_cu3zaenytdST5Xg0rve66blwdQ15z3rXO0MU7XRjQ9Mia6RXe1615hW96ou19DqpheNCYLJa3J_yi1dfs-Akz1ELN0Hl2Cc0bZaK8MV44W8-4fcjXNOpZwVnBVtUukCVSfI5xExQ2-POR5cXixn9lW6xZ3dR3uWXvjbc-jcHSD8pc-WC6BPABQJLxGyRR8heQgxg59sGON_ov8AHceQHA</recordid><startdate>20080201</startdate><enddate>20080201</enddate><creator>Nagao, S.</creator><creator>Nishii, K.</creator><creator>Yoshihara, D.</creator><creator>Kurahashi, H.</creator><creator>Nagaoka, K.</creator><creator>Yamashita, T.</creator><creator>Takahashi, H.</creator><creator>Yamaguchi, T.</creator><creator>Calvet, J.P.</creator><creator>Wallace, D.P.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20080201</creationdate><title>Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat</title><author>Nagao, S. ; 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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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17943077</pmid><doi>10.1038/sj.ki.5002629</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | ADPKD Animals Apoptosis - drug effects Blood Urea Nitrogen calcium Calcium - metabolism Calcium Channel Blockers - adverse effects Cell Proliferation - drug effects cell signaling cyclic AMP Cyclic AMP - metabolism Cysts - chemically induced Disease Progression Female Kidney - drug effects Kidney - metabolism Kidney - pathology Male MAP Kinase Signaling System - drug effects Organ Size - drug effects Polycystic Kidney Diseases - chemically induced Polycystic Kidney Diseases - metabolism Polycystic Kidney Diseases - pathology proliferation Proto-Oncogene Proteins B-raf - metabolism Rats Rats, Sprague-Dawley Verapamil - adverse effects |
| title | Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat |
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