TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus
Alexandra E. Hochstetler, Hillary M. Smith, Daniel C. Preston, Makenna M. Reed, Paul R. Territo, Joon W. Shim, Daniel Fulkerson, Bonnie L. Blazer-Yost
Alexandra E. Hochstetler, Hillary M. Smith, Daniel C. Preston, Makenna M. Reed, Paul R. Territo, Joon W. Shim, Daniel Fulkerson, Bonnie L. Blazer-Yost
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Research Article Neuroscience Therapeutics

TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus

Abstract

Hydrocephalus is a serious condition that impacts patients of all ages. The standards of care are surgical options to divert, or inhibit production of, cerebrospinal fluid; to date, there are no effective pharmaceutical treatments, to our knowledge. The causes vary widely, but one commonality of this condition is aberrations in salt and fluid balance. We have used a genetic model of hydrocephalus to show that ventriculomegaly can be alleviated by inhibition of the transient receptor potential vanilloid 4, a channel that is activated by changes in osmotic balance, temperature, pressure and inflammatory mediators. The TRPV4 antagonists do not appear to have adverse effects on the overall health of the WT or hydrocephalic animals.

Authors

Alexandra E. Hochstetler, Hillary M. Smith, Daniel C. Preston, Makenna M. Reed, Paul R. Territo, Joon W. Shim, Daniel Fulkerson, Bonnie L. Blazer-Yost

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Figure 6

mRNA expression of water and electrolyte transporters and channels in native rat choroid plexus.

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mRNA expression of water and electrolyte transporters and channels in na...
(A–C) RT-PCR gels showing the presence of selected apical transporters (A), basolateral transporters (B), and potassium channels (C) in native rat choroid plexus tissue. (D) qPCR of WT and hydrocephalic (Hom) untreated (Untr) and RN 1734–treated (RN) choroid plexus (n = 3, each in triplicate) with TRPV4, AQP1 (WT RN, n = 2), NKCC1, TMEM16A, IK, Na+/K+ ATPase α (NKa) subunit and Na+/K+ ATPase β (NKb) subunit primers. RN treated choroid plexus tissue from homozygous animals showed a significant decrease (***P < 0.0001) in TRPV4 mRNA expression relative to untreated WT tissue. RN and Untr tissue from homozygous animals demonstrated significant (*P < 0.05) increases in AQP1 mRNA expression relative to untreated WT tissue. RN treated WT and Untr homozygous tissue also exhibited significant (*P < 0.05) increases in NKCC1 mRNA expression relative to untreated WT tissue. RN treated homozygous tissue had a significant (**P < 0.01) decrease in IK mRNA relative to untreated WT tissue. NKa mRNA increased significantly (**P < 0.01) in RN treated WT animals relative to untreated WT tissue. TMEM16A and NKb did not have any significant changes in mRNA regardless of genotype or treatment. Significance values were determined by unpaired t test calculated in Prism. AQP1, aquaporin 1; ATP1A1/B2, ATPase Na+/K+ Transporting Subunits α1/β2; LRRC8A, volume regulated anion channel; NKCC1, sodium, potassium, chloride cotransporter 1; TMEM16A, anoctamin-1 chloride channel; TRPV4, transient receptor potential vanilloid 4; AE2, acid exchanger 2; NBCe2, sodium bicarbonate cotransporter; NCBE, electrogenic sodium bicarbonate exchanger 1; BK, large conductance potassium channel; IK, intermediate conductance potassium channel; SK1/2/3, small conductance potassium channels 1/2/3. Primer information for can be found in Supplemental Table 1.