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Review
. 2013 Feb;465(2):177-86.
doi: 10.1007/s00424-012-1190-z. Epub 2012 Dec 4.

Novel insights into TRPV4 function in the kidney

Oleh Pochynyuk  1 , Oleg Zaika, Roger G O'Neil, Mykola Mamenko
Affiliations
Review

Novel insights into TRPV4 function in the kidney

Oleh Pochynyuk et al. Pflugers Arch. 2013 Feb.

Abstract

Kidneys are complex highly organized paired organs of nearly one million nephrons each. They rigorously process about 180 l of plasma daily to keep whole body homeostasis. To effectively perform such a titanic work, kidneys rely on mechanisms able to sense dynamic changes in composition and flow rates of protourine along the renal tubule. It is envisioned that Ca(2+)-permeable transient receptor potential (TRP) channels, and specifically mechanosensitive TRPV4, can serve to interpret these external mechanical cues in the form of elevated intracellular Ca(2+) concentration. This, in turn, initiates multiple cellular responses and adaptation mechanisms. The current review summarizes up-to-date knowledge about the sites of TRPV4 expression in renal tissue as well as discusses the functional role of the channel in cellular responses to hypotonicity and tubular flow. We will also provide insights as to how TRPV4 fits into classical polycystin mechanosensory complex in cilia and will speculate about previously underappreciated clinical implication of pharmacological TRPV4 targeting in treatment of polycystic kidney disease.

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Conflict of interest statement

Disclosures

Authors declare that no conflicts of interest exist.

Figures

Figure 1
Figure 1
Proposed scheme, illustrating the involvement of TRPV4 in mechanosensitivity in the distal nephron cells. PLA2 – phospholipase A2, AA – arachidonic acid, CYP450 – cytochrome P450 epoxygenase, EETs – epoxyeicosatrienoic acids, formula image – proline rich domain, PC-1 – polycystin-1, PKC – protein kinase C, PLC- phospholipase C, P2Y2R – P2Y2 receptor, Cx30 – connexin 30 hemichannel. In the kidney TRPV4 forms a heteromeric channel with polycystin-2 (TRPP2), which is a part of a larger mechanosensitive complex also involving of PC-1. Mechanical stress stimulates PLA2 – CYP450 pathway, which metabolizes AA to EETs. EETs activate TRPV4 channel to elicit Ca2+ influx in response to hypotonicity or elevated flow. This activation can be prevented by interaction of TRPV4 N-terminal proline rich domain with PACSIN 3 protein. On the other hand, mechanical stimuli induce ATP release from distal nephron cells through Cx30 hemichannels. Locally released ATP binds to purinergic P2Y2 receptors on the apical membrane of renal epithelium. This leads to Gq/11 dependent activation of PLC and, likely, PKC and further augmenting TRPV4 activity.
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