Deficient transient receptor potential vanilloid type 4 function contributes to compromised [Ca2+] homeostasis in human autosomal‐dominant polycystic kidney disease cells. Issue 8 (19th March 2018)

• Record Type: Journal Article
• Authors: Tomilin, Viktor; Reif, Gail A.; Zaika, Oleg; Wallace, Darren P.; Pochynyuk, Oleh
• Is Part Of: FASEB journal. Volume 32:Issue 8(2018)
• Page Start: 4612
• Page End: 4623
• Publication Date: 2018-03-19
• Subjects: distal tubule -- polycystins -- glycosylation; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201701535RR
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : Autosomal‐dominant polycystic kidney disease (ADPKD) is a devastating disorder that is charac‐terized by a progressive decline in renal function as a result of the development of fluid‐filled cysts. Defective flow‐mediated [Ca 2 +]i responses and disrupted [Ca 2 +]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 [Ca 2 +]i responses in murine distal renal tubule cells. To determine whether compromised TRPV4 function contributes to aberrant Ca 2+ 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 Ca 2+ influxes were drastically reduced in ADPKD cells, which correlated with distorted [Ca 2+ ]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 [Ca 2+ ]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 [Ca 2+ ]i dy‐namics. We propose that TRPV4 stimulation may be beneficial for restoring [Ca 2+ ]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 ho‐meostasis in human autosomal‐dominant polycystic kidney disease cells. FASEB J . 32, 4612‐4623 (2018). www.fasebj.org