The role of aquaporin‐4 and transient receptor potential vaniloid isoform 4 channels in the development of cytotoxic edema and associated extracellular diffusion parameter changes

Abstract

The proper function of the nervous system is dependent on the balance of ions and water between the intracellular and extracellular space (ECS). It has been suggested that the interaction of aquaporin‐4 (AQP4) and the transient receptor potential vaniloid isoform 4 (TRPV4) channels play a role in water balance and cell volume regulation, and indirectly, of the ECS volume. Using the real‐time iontophoretic method, we studied the changes of the ECS diffusion parameters: ECS volume fraction α (α = ECS volume fraction/total tissue volume) and tortuosity λ (λ2 = free/apparent diffusion coefficient) in mice with a genetic deficiency of AQP4 or TRPV4 channels, and in control animals. The used models of cytotoxic edema included: mild and severe hypotonic stress or oxygen‐glucose deprivation (OGD) in situ and terminal ischemia/anoxia in vivo. This study shows that an AQP4 or TRPV4 deficit slows down the ECS volume shrinkage during severe ischemia in vivo. We further demonstrate that a TRPV4 deficit slows down the velocity and attenuates an extent of the ECS volume decrease during OGD treatment in situ. However, in any of the cytotoxic edema models in situ (OGD, mild or severe hypotonic stress), we did not detect any alterations in the cell swelling or volume regulation caused by AQP4 deficiency. Overall, our results indicate that the AQP4 and TRPV4 channels may play a crucial role in severe pathological states associated with their overexpression and enhanced cell swelling. However, detailed interplay between AQP4 and TRPV4 channels requires further studies and additional research.

TRPV4 channels mediate the mechanoresponse in retinal microglia

“…Another possibility is adenosine, acting via A2A receptors, which induces branch retraction during inflammatory states but has less effect on ramified microglia in the healthy brain (Orr, Orr, Li, Gross, & Traynelis, 2009). In any case, our data suggest that inhibition of retinal TRPV4 channels profoundly affects microglial morphology, potentially impeding the transition towards proinflammatory‐like phenotypes in tissues exposed to hypotonic gradients (e.g., Chmelova et al, 2019; Gankam‐Kengne et al, 2010). The precise molecular mechanisms that mediate volume‐dependent process remodeling should be established in microglia‐specific mouse knockout lines.…”

“…Identified by its ability to transduce hypotonic stimuli (HTS) in recombinant cells (Strotmann, Harteneck, Nunnenmacher, Schultz, & Plant, 2000), TRPV4 was shown to regulate cell swelling in many cell types, including some macroglia (Becker, Blasé, Bereiter‐Hahn, & Jendrach, 2005; Hoshi et al, 2018; Jo et al, 2015; Lee, Stowers, & Chaudhuri, 2019, but see Chmelova et al, 2019). We investigated the dynamics of microglial volume regulation by exposing eGFP + cells to HTS while keeping the external solution's ionic strength constant (Jo et al, 2015; Ryskamp et al, 2011).…”

Aquaporin Expression, Regulation and Function in the Intervertebral Disc

“…AQP4 and TRPV4 function is linked to osmosensing and the adaptation to extracellular osmolality of astrocytes (Benfenati et al, 2011a;Jo et al, 2015;Mola et al, 2016;Chmelova et al, 2019), and results described here also indicate there may be similar mechanisms employed by NP cells.…”

Decrease in AQP4 expression level in atrophied skeletal muscles with innervation

“…Indeed, in the present study, the expression of several ion channels, such as TRPV4, NKCC1 and Na + /K + ‐ATPase α2, significantly decreased in the immobilized skeletal muscles. Moreover, osmotic homeostasis and cell volume were respectively regulated by functional interaction between AQP4 and these ion channels (Chmelova et al, 2019; Illarionova et al, 2010; Jo et al, 2015; Mola et al, 2016; Strohschein et al, 2011; Yan et al, 2018; Zhang et al, 2016). Therefore, the present study suggested that water and ion transport may decrease due to the lower expression of AQP4 and related ion channels in the immobilized skeletal muscles.…”