Vasopressin-2 receptor antagonists in autosomal dominant polycystic kidney disease: from man to mouse and back

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy, with an estimated prevalence of 1:1000. The disease is characterized by the development of multiple cysts from all nephron segments leading to the enlargement of both kidneys and replacement of normal parenchyma (see [1]). Change in total kidney volume over time is the strongest predictor of renal function decline in ADPKD [2]. Glomerular filtration rate remains preserved up to the age of 40 years in most patients because glomerular hyperfiltration in functioning nephrons compensates for the ongoing loss of renal tissue, until end-stage renal failure ensues in >50% of patients, usually in their fifth decade. Mutations in the PKD1 gene account for ~85% of the affected families, whereas the remaining cases are caused by mutations in PKD2. PKD1 encodes polycystin-1, an integral membrane protein with a large extracellular domain that probably functions as a receptor and/or an adhesion molecule, whereas PKD2 encodes polycystin-2, a non-selective cation channel belonging to the family of transient receptor potential channels. The polycystins are located in the primary cilium and interact to form a mechanosensory complex that is involved in intracellular Ca 21 homeostasis and various signalling pathways. Disruption of the complex leads to cyst development and enlargement resulting from tubular cell proliferation and transepithelial fluid secretion. The progressive understanding of these pathways has led to spectacular advances in the prospective treatment for ADPKD, including the blockade of vasopressin 2 receptor (V2R) to decrease the intracellular level of 3#-5#-cyclic adenosine monophosphate (cAMP) in cyst-lining tubular cells [1]. Vasopressin and cAMP in ADPKD