Calcimimetic inhibits late-stage cyst growth in ADPKD.
In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.
Gattone
Vincent H
VH
Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA. vgattone@iupui.edu
Chen
Neal X
NX
Sinders
Rachel M
RM
Seifert
Mark F
MF
Duan
Danxia
D
Martin
David
D
Henley
Charles
C
Moe
Sharon M
SM
D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002118:Calcium / Q000819:agonists* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006961:Hyperparathyroidism / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D010281:Parathyroid Hormone / Q000378:metabolism; D010627:Phenethylamines; D007690:Polycystic Kidney Diseases / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control*; D011437:Propylamines; D051381:Rats; D011919:Rats, Inbred Strains; D044169:Receptors, Calcium-Sensing / Q000187:drug effects / Q000378:metabolism*; D012720:Severity of Illness Index
D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D002118:Calcium