Advances in the understanding of cystogenesis and availability of animal models orthologous to human
autosomal dominant polycystic kidney disease (
ADPKD) and recessive
polycystic kidney disease (
ARPKD) will likely facilitate the development of treatments for these diseases.
Proteins mutated in
ADPKD and
ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular
calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/
MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing
polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/
MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels,
Raf kinase activities and ERK phosphorylation are increased in
polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras-Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases
B-Raf kinase activity and ERK phosphorylation in
polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/
MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct.
Vasopressin is the major
adenylyl cyclase agonist in the collecting duct principal cells via a
V2 receptor. OPC31260, a
V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of
polycystic kidney disease, three of which are orthologous to human diseases (PCK rat,
ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/- mouse,
ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.