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.

A potential strategy for reducing cysts in autosomal dominant polycystic kidney disease with a CFTR corrector

“…Misregulation of Ca 2ϩ -dependent signal transduction is associated with cyst formation (27,30). To determine whether VX-809 alters Ca 2ϩ movement, we treated the cells with ATP, which stimulates purinergic receptors (31) and found ( Fig.…”

“…Misregulation of Ca 2ϩ is associated with cyst formation in ADPKD (35), with some investigators reporting that disruption of Ca 2ϩ signaling is the primary event that supports increased cyst growth (30). Several studies have shown that a reduction in the function of either PC1 or PC2 leads to dysregulation of Ca 2ϩ signaling (see Ref.…”

Role of calcium in adult onset polycystic kidney disease

“…Misregulation of Ca 2+ is associated with cyst formation in ADPKD[13], with some investigators reporting that disruption of Ca 2+ signaling is the primary event that supports increased cyst growth[14]. Several studies have shown that a reduction in the function of either PC1 or PC2 leads to dysregulation of Ca 2+ signaling (see [9] for a review).…”

“…The null cells (PN) stably express the Cre recombinase, and the control cells (PH) are from the original clone, which is heterozygous for the expression of PC1 [18, 19]. Others have shown that expression of the C-terminal fragment of PC1 can cause an increase in basal levels of intracellular Ca 2+ and induce abnormal Ca 2+ oscillations, which also result in increases in cell signaling [14]. Thus, there appears to be a dichotomy of thought on how Ca 2+ plays a role in ADPKD with some thinking that Ca 2+ restriction causes cyst growth and others that enhanced release of Ca 2+ from the ER is the major factor which fuels cyst growth.…”

Treatment of autosomal recessive and autosomal dominant polycystic kidney disease

“…В настоящее время широко обсуждаются вопросы лечения наследственных заболеваний [1,2]. Лечение, воздействующее на основные патогенетические звенья роста кист при поликистозе почек, направлено: 1) на уменьшение пролиферации эпителиальных клеток канальцев и секреции жидкости за счет снижения уровня внутриклеточного Ca 2+ ; 2) на подавление эпидермального фактора роста (EGFR), уменьшение уровня цАМФ и снижение активности cSrc (тирозинкиназы, принимающей участие в процессе клеточного роста; cSrc является посредником в перекрестной связи EGFR и G-белка цАМФ) [7,23,24]. Кроме того, обсуждается поиск путей воздействия на восстановление клеточно-клеточных и клеточно-матриксных связей, угнетение прогрессирующего интерстициального фиброза, связанного с повреждением макрофагов, и подавление пути mTOR (mammalian target of rapamycin -мишени рапамицина млекопитающих) [23,25].…”