Polycystins in disease mechanobiology

Abstract

Distorted mechanotransduction represents the molecular hallmark of disease mechanobiology and is displayed with common features during the development of various pathophysiologies. Polycystins constitute a family of mechanosensitive proteins that facilitate pathogenic signal transduction mechanisms. The main representatives of the family are polycystin‐1 (PC1) and polycystin‐2 (PC2), which function as a mechano‐induced membrane receptor and a calcium‐permeable ion channel, respectively. PC1 and PC2 mediate extracellular mechanical stimulation, induce intracellular molecular signaling and evoke corresponding gene transcription. Recent reports reveal that polycystin‐mediated signaling does not occur in polycystic kidney disease only, where it is most prominently studied. It is also present during the development of clinical entities such as endothelial dysfunction and atheromatosis, deregulation of osteoblast differentiation, cancer development, and psoriasis. In this study, we highlight emerging data that support the overall contribution of polycystins to disease mechanobiology and suggest further exploration of this protein family in diseases generated from force‐bearing tissue structures.

Shear stress induced by fluid flow produces improvements in tissue-engineered cartilage

“…Therefore, we also investigated and verified the upregulation of IHH expression in the bovine-derived neocartilage constructs via RT-PCR (figure 8(b)). The activation of the PC1/2 complexes by fluid flow perturbation would result in a greater influx of Ca 2+ ions, than unstimulated chondrocytes [41,42], initiating a cascade of upregulated extracellular matrix producing and remodeling genes and proteins in chondrocytes [43][44][45], leading to the formation of mechanically robust neocartilage (figure 8(c)).…”

Polycystins, mechanotransduction and cancer development

“…This 'aggregate' creates non-selective cation channels pervious to Ca 2+ ions. 17,18 Among the biological properties that characterize cancer cells is the continuous transmission of signals that promote proliferation, resistance to apoptosis and activation of invasive mechanisms and metastasis. 19 Participation of polycystins in pivotal cellular functions such as proliferation, apoptosis, mediation of intercellular interactions, communication with the ECM and cell orientation, suggest the potential contribution of this family of proteins to tumorigenic processes, especially invasion and metastasis.…”

“…PC1 and PC2 interact physically in vivo via their C‐terminus generating heterodimeric complexes at the cell membrane and at epithelial formations known as primary cilia. This ‘aggregate’ creates non‐selective cation channels pervious to Ca 2+ ions 17,18 …”

Polycystins and Mechanotransduction in Human Disease

“…PC1 and PC2 are expressed in a variety of tissues of the cardiovascular system, and they have been implicated in the pathophysiology of extrarenal vascular manifestations of ADPKD, as well as other cardiovascular diseases (Table 1) [59]. Primary cilia in the endothelium sense fluid flow, and PC1 regulates calcium influx along with the production of the vasodilator nitric oxide [60].…”