Polycystin-1 and -2 Dosage Regulates Pressure Sensing

Abstract

Autosomal-dominant polycystic kidney disease, the most frequent monogenic cause of kidney failure, is induced by mutations in the PKD1 or PKD2 genes, encoding polycystins TRPP1 and TRPP2, respectively. Polycystins are proposed to form a flow-sensitive ion channel complex in the primary cilium of both epithelial and endothelial cells. However, how polycystins contribute to cellular mechanosensitivity remains obscure. Here, we show that TRPP2 inhibits stretch-activated ion channels (SACs). This specific effect is reversed by coexpression with TRPP1, indicating that the TRPP1/TRPP2 ratio regulates pressure sensing. Moreover, deletion of TRPP1 in smooth muscle cells reduces SAC activity and the arterial myogenic tone. Inversely, depletion of TRPP2 in TRPP1-deficient arteries rescues both SAC opening and the myogenic response. Finally, we show that TRPP2 interacts with filamin A and demonstrate that this actin crosslinking protein is critical for SAC regulation. This work uncovers a role for polycystins in regulating pressure sensing.

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

“…Electrophysiology. Electrophysiological procedure has been previously described elsewhere [24,32]. Renal mechanotransduction R. Peyronnet et al scientific report…”

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

“…We previously showed that Pkd1 gene disruption in vascular SMCs results in a reduced myogenic tone. 18 Functional roles for the polycystins in mechanosensation have been proposed in ECs as well as SMCs. In ECs, the proteins are involved in fluid shear stress sensing, thereby regulating calcium signaling and nitric oxide release.…”

“…In mice with reduced Pkd1 expression in SMCs, stretch-activated channel (SAC) activity was decreased and the threshold pressure for myogenic contraction was significantly shifted to higher pressure values. 18 The ratio of polycystin-1/polycystin-2 regulates SACs activity, as polycystin-2 inhibits channel opening, whereas polycystin-1 reverses this inhibition. 18 It is likely that alterations in intracellular Ca 2 þ homeostasis contribute to the vascular phenotype in PKD.…”

“…18 The ratio of polycystin-1/polycystin-2 regulates SACs activity, as polycystin-2 inhibits channel opening, whereas polycystin-1 reverses this inhibition. 18 It is likely that alterations in intracellular Ca 2 þ homeostasis contribute to the vascular phenotype in PKD. 20,21 In this study, we show that disruption of the Pkd1 gene in these cells did not induce gross structural abnormalities in blood vessels, even not when Pkd1 was disrupted in ECs, as well.…”

Cils et kystes rénaux

“…En réponse au flux d'urine, la flexion du cil déclencherait une augmentation transitoire du calcium intracellulaire, provenant du réticulum endoplasmique et du compartiment extracellulaire ; cette réponse requiert l'intégrité du cil, au moins dans les cellules en culture [31,32]. Ce rôle de senseur de la pression du flux dépend du taux respectif des protéines PC1 et PC2 [4,5,33]. Ainsi, chez les souris Pkd1 -/-, le cil des cellules des tubules proximaux se forme normalement, mais la réponse calcique qu'il induit est défectueuse [34].…”