Deficient transient receptor potential vanilloid type 4 function contributes to compromised [Ca²⁺] homeostasis in human autosomal‐dominant polycystic kidney disease cells

Abstract

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 [Ca] responses and disrupted [Ca] 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] responses in murine distal renal tubule cells. To determine whether compromised TRPV4 function contributes to aberrant Ca 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 influxes were drastically reduced in ADPKD cells, which correlated with distorted [Ca] 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] 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] dynamics. We propose that TRPV4 stimulation may be beneficial for restoring [Ca] 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 [Ca] homeostasis in human autosomal-dominant polycystic kidney disease cells.

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

“…Yamaguchi et al [ 61 ] showed that steady-state [Ca 2+ ] i levels are 20 nM lower in cyst-derived ADPKD cells (57 ± 2 nM) compared with normal human kidney cells (77 ± 2 nM). These findings are similar to the results of Tomilin et al, also obtained in ADPKD [ 62 ]. On the other hand, in ARPKD, using cystic monolayers freshly isolated from PCK rats, Palygin et al demonstrated that basal concentration of Ca 2+ is ∼120 nM, while Zaika et al reported a lower (∼90 nM) level in the same model [ 63 , 64 ].…”

“…There is evidence that improper flow-mediated [Ca 2+ ] i responses are involved in both ARPKD and ADPKD cystogenesis [ 37 ], potentially through the effects on the transduction of the flow sensation by the renal cilia, or mechanosensitive properties of the ion channels and transporters themselves. The transient receptor potential vanilloid type 4 (TRPV4) channels could play an important modulatory role in the process of mechanosensation [ 62 , 64 ]. TRPV4 is a Ca 2+ -permeable, nonselective cation channel that can be activated by various chemical, osmotic and mechanical signals.…”

TRPC3 determines osmosensitive [Ca2+]i signaling in the collecting duct and contributes to urinary concentration

“…Expression and functional activity of several TRP channels, including TRPC3, TRPC6, and TRPV4, have been reported in the native CD cells and CD-derived cultures [16, 17]. Accumulated evidence has demonstrated that TRPV4 is indispensable for flow-induced [Ca 2+ ] i elevations [17–19]. However, TRPV4 -/- mice do not demonstrate measurable defects in the renal water handling [20, 21] indicating that distinct molecular mechanisms are involved in sensing changes in flow and osmolarity in the CD.…”

With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron

“…Abundant cumulative evidence shows that TRPV4 serves as a mechanical sensor of tubular flow in the ASDN [5][6][7][8][9]. TRPV4 dysfunction compromises [Ca 2+ ] i homeostasis and abolishes flow-induced elevations of Cells 2021, 10, 2 of 17 [Ca 2+ ] i in native freshly isolated split-opened ASDN of rodents and in primary cultures of human distal nephron cells [5,10,11].…”