title: Role of calcium in polycystic kidney disease: From signaling to pathology.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 (PC1), a large multi-functional membrane receptor protein able to regulate ion channel complexes, whereas polycystin-2 (PC2), encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum (ER). In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this field could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.
authors.affiliation: Alessandra Mangolini, Lucia de Stephanis, Gianluca Aguiari, Department of Biomedical and Surgical Specialty Sciences, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangolini
authors.affiliation: Alessandra Mangolini, Lucia de Stephanis, Gianluca Aguiari, Department of Biomedical and Surgical Specialty Sciences, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: de Stephanis
authors.affiliation: Alessandra Mangolini, Lucia de Stephanis, Gianluca Aguiari, Department of Biomedical and Surgical Specialty Sciences, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Aguiari
keywords: Autosomal dominant polycystic kidney disease; Calcium signaling; Cell growth; Non-capacitative calcium entry; cAMP