Molecular basis of hereditary cystic kidney diseases

Abstract

The inherited cystic nephropathies (ICNs) are caused by gene mutations determinant to the development of renal epithelial cell abnormalities, alterations that create the biological conditions necessary to cyst formation. The identification of genes mutated in these diseases and the characterization of their protein products have been allowing the elucidation of mechanisms involved in their pathogenesis. The current review focus on the genetic basis and molecular pathogenesis of such illnesses, though it also briefly addresses clinical and epidemiological aspects of the ICNs with higher medical and socioeconomical impact. Within this disease set, we will approach autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, nephronophthises, autosomal dominant tubule-interstitial kidney disease, von Hippel-Lindau disease, and tuberous sclerosis complex. These ICNs present overlapping of clinical manifestations and share pathways and molecular defects. Among their common features, we will focus on the central role of abnormalities affecting the primary apical cilium and intracellular signaling pathways responsible for fundamental alterations in cell phenotype. When highlighting the advances in molecular and cellular pathogenesis of ICNs, we will critically discuss the establishment, the roles and the implications of the defective cytosolic calcium homeostasis; hyperproliferative cell response to cyclic AMP; high cell proliferation and apoptosis rates; extracellular matrix alterations; cell polarity abnormalities; and transepithelial fluid secretion. The knowledge accumulated in the last two decades brought a new molecular and cellular scenario to the ICNs, creating the required platform to develop preclinical assays. Such studies, in turn, have been supporting the performance of robust clinical trials which have been opening promising therapeutic perspectives.