Polycystins and Molecular Basis of Autosomal Dominant Polycystic Kidney Disease

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal monogenic disorder. It is characterized by progressive, bilateral renal cystic expansion followed by gradual loss of renal function after decades of life, while its systemic nature is reflected by extra-renal manifestations typically involving liver and the cardiovascular system. Cyst formation is triggered by mutations in the PKD1 or PKD2 genes. In most cysts, if not all, cystogenesis follows a two-hit model in developmental kidneys, while in the mature organ broad and fast cyst formation requires a third hit such as kidney injury. The first hit is represented by the germline mutation whereas a somatic total or partial inactivation of the previously normal allele constitutes the second event, a process that is consistent with the focal nature of ADPKD cystogenesis. PKD1 encodes polycystin-1 (PC1), a likely transmembrane mechano-sensor receptor comprised of a singular combination of structural domains present in other proteins. PKD2, in turn, encodes polycystin-2 (PC2), a non-selective cationic channel permeable to calcium composed by six transmembrane helices and intracytosolic C- and N-termini. In the primary cilium, PC1 regulates cell calcium influx by physically interacting with PC2 through their intracytosolic domains. Disruption of calcium cellular homeostasis increases cAMP cytosolic levels and affects cell cycle, leading to increased cell proliferation and transepithelial fluid secretion. In addition, disruption of PC1 C-terminus interactions with components of Wnt, mTOR, STAT3 and JAK2/STAT1 pathways is translated into a number of intracellular pathway abnormalities. In the same line, interactions between the PC2 C- and N-termini with ERK/B-Raf, GSK3β and other partners lead to disturbed cell proliferation, apoptosis and cell polarity. Mutations in PKD1 can result, moreover, in cell adhesion and extracellular matrix alterations, due to the role of PC1 extracellular domains in cell-cell and cell-matrix contact. Defects in the mentioned pathways can also impact oriented cell division, contributing to cyst growth.