title: L-type calcium channel modulates cystic kidney phenotype.
abstract: In polycystic kidney disease (PKD), abnormal proliferation and genomic instability of renal epithelia have been associated with cyst formation and kidney enlargement. We recently showed that L-type calcium channel (CaV1.2) is localized to primary cilia of epithelial cells. Previous studies have also shown that low intracellular calcium level was associated with the hyperproliferation phenotype in the epithelial cells. However, the relationship between calcium channel and cystic kidney phenotype is largely unknown. In this study, we generated cells with somatic deficient Pkd1 or Pkd2 to examine ciliary CaV1.2 function via lentiviral knockdown or pharmacological verapamil inhibition. Although inhibition of CaV1.2 expression or function did not change division and growth patterns in wild-type epithelium, it led to hyperproliferation and polyploidy in mutant cells. Lack of CaV1.2 in Pkd mutant cells also decreased the intracellular calcium level. This contributed to a decrease in CaM kinase activity, which played a significant role in regulating Akt and Erk signaling pathways. Consistent with our in vitro results, CaV1.2 knockdown in zebrafish and Pkd1 heterozygous mice facilitated the formation of kidney cysts. Larger cysts were developed faster in Pkd1 heterozygous mice with CaV1.2 knockdown. Overall, our findings emphasized the importance of CaV1.2 expression in kidneys with somatic Pkd mutation. We further suggest that CaV1.2 could serve as a modifier gene to cystic kidney phenotype.
authors.affiliation: Department of Physiology and Pharmacology, The University of Toledo, Toledo, OH, USA.
authors.forename: Xingjian
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Muntean
authors.affiliation: Department of Physiology and Pharmacology, The University of Toledo, Toledo, OH, USA.
authors.forename: Munaf S
authors.initials: MS
authors.lastname: Aal-Aaboda
authors.affiliation: Department of Biochemistry and Cancer Biology, USA.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pharmacology, The University of Toledo, Toledo, OH, USA; Department of Medicinal and Biological Chemistry, The University of Toledo, Toledo, OH, USA. Electronic address: Surya.Nauli@UToledo.Edu.
authors.forename: Surya M
authors.initials: SM
authors.lastname: Nauli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002923:Cilia / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050396:TRPP Cation Channels / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D002118:Calcium; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051057:Proto-Oncogene Proteins c-akt; D050396:TRPP Cation Channels; D014700:Verapamil; C514350:CACNA1C protein, mouse
keywords: CaV1.2 L-type calcium channel; Cystic kidney; Modifier gene; PKD; Primary cilia