title: Calcimimetics inhibit renal pathology in rodent nephronophthisis.
abstract: The development and progression of renal cysts appears to be driven by reduced cellular calcium and increased cyclic adenosine monophosphate (cAMP) from G-protein-coupled receptors. To test whether treatment with a calcimimetic that stimulates the G-protein-coupled calcium-sensing receptor might normalize cystic epithelial cell intracellular calcium and cAMP, thereby inhibiting cyst progression, we used pcy mice. These animals develop cysts principally in the collecting duct, as do humans with nephronophthisis (NPHP). We administered the calcimimetic R-568 mixed in their food at early or late stages in the pathogenesis of cyst formation. The treatment reduced cyst enlargement, and the early treatment inhibited development of renal fibrosis. Although the effect of later treatment was more modest, both stages of the disease responded positively to treatment. Additionally, R-568 decreased total kidney cAMP in the pcy mice and, in vitro, decreased cAMP levels and cell proliferation, while increasing intracellular calcium in immortalized human autosomal recessive polycystic kidney disease renal epithelial cells. The latter two effects were unique to R-568 and not replicated by raising extracellular calcium. Thus, treating pcy mice with R-568 was effective in reducing cyst progression in this rodent model of NPHP. Direct studies will be needed to determine whether these results can be applied to the human disease.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, 1001 West 10th Street, Indianapolis, IN 46202, USA. xuechen@iupui.edu
authors.forename: Neal X
authors.initials: NX
authors.lastname: Chen
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Moe
authors.forename: Tracy
authors.initials: T
authors.lastname: Eggleston-Gulyas
authors.forename: Xianming
authors.initials: X
authors.lastname: Chen
authors.forename: William D
authors.initials: WD
authors.lastname: Hoffmeyer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bacallao
authors.forename: Brittney S
authors.initials: BS
authors.lastname: Herbert
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D057966:Calcimimetic Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D016547:Kinesins / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D010627:Phenethylamines; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011437:Propylamines; D044169:Receptors, Calcium-Sensing / Q000819:agonists
chemical_list: D000814:Aniline Compounds; D057966:Calcimimetic Agents; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D000242:Cyclic AMP; C528698:nephrocystin-3, mouse; D016547:Kinesins