Deficient transient receptor potential vanilloid type 4 function contributes to compromised [Ca²⁺]_i homeostasis in...

Autosomal-dominant polycystic kidney disease (ADPKD) is a devastating disorder that is characterized by a progressive decline in renal function as a result of the development of fluid-filled cysts. Defective flow-mediated [Ca²⁺]_i responses and disrupted [Ca²⁺]_i homeostasis have been repeatedly associated with cyst progression in ADPKD. We have previously demonstrated that the transient receptor potential vanilloid type 4 (TRPV4) channel is imperative for flow-mediated [Ca²⁺]_i responses in murine distal renal tubule cells. To determine whether compromised TRPV4 function contributes to aberrant Ca²⁺ regulation in ADPKD, we assessed TRPV4 function in primary cells that were cultured from ADPKD and normal human kidneys (NHKs). Single-channel TRPV4 activity and TRPV4-dependent Ca²⁺ influxes were drastically reduced in ADPKD cells, which correlated with distorted [Ca²⁺]_i signaling. Whereas total TRPV4 protein levels were comparable in NHK and ADPKD cells, we detected a marked decrease in TRPV4 glycosylation in ADPKD cells. Tunicamycin-induced deglycosylation inhibited TRPV4 activity and compromised [Ca²⁺]_i signaling in NHK cells. Overall, we demonstrate that TRPV4 glycosylation and channel activity are diminished in human ADPKD cells compared with NHK cells, and that this contributes significantly to the distorted [Ca²⁺]_i dynamics. We propose that TRPV4 stimulation may be beneficial for restoring [Ca²⁺]_i homeostasis in cyst cells, thereby interfering with ADPKD progression.-Tomilin, V., Reif, G. A., Zaika, O., Wallace, D. P., Pochynyuk, O. Deficient transient receptor potential vanilloid type 4 function contributes to compromised [Ca²⁺]_i homeostasis in human autosomal-dominant polycystic kidney disease cells.