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.