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.