Region‐Specific Changes in Transient Receptor Potential Vanilloid Channel Expression in the Vasopressin Magnocellular System in Hepatic Cirrhosis‐Induced Hyponatraemia

Abstract

The purpose of this study was to measure the expression of transient receptor potential (TRP) channels in the magnocellular neurons of the paraventricular (PVN) and supraoptic nucleus (SON) in an animal model of hepatic cirrhosis associated with inappropriate vasopressin (AVP) release. In these studies we used chronic bile duct ligation (BDL) in the rat, a commonly used model of hepatic cirrhosis, associated with elevated plasma AVP. This study tested the hypothesis that changes in TRPV channel expression may be related to inappropriate AVP release in BDL rats. To test our hypothesis, we utilized laser capture microdissection of AVP neurons in the PVN and SON and Western blot analysis from brain punches. Laser capture microdissection and qRT-PCR demonstrated elevated TRPV2 mRNA in the PVN and SON of BDL as compared to sham ligated controls. AVP transcription was also increased as determined using intron specific primers to measure heteronuclear RNA. Immunohistochemistry demonstrated increased AVP and TRPV2 positive cells in both the PVN and SON after BDL. Also, there was an increased co-expression of TRPV2 and AVP cells after BDL. However, there was no change in the colocalization counts of TRPV2 and OXY in both the magnocellular regions evaluated. In the SON but not the PVN, transcription levels of TRPV4 was also significantly increased in BDL rats Western Blot analysis of punches containing the PVN and SON revealed that TRPV2 protein content was significantly increased in these brain regions in BDL rats compared to sham. Our data suggests that regionally specific changes in TRPV expression in the MNC AVP neurons could alter their osmosensing ability.

ΔFosB in the supraoptic nucleus contributes to hyponatremia in rats with cirrhosis

“…In a previous study, experimental cirrhosis in the rat was not associated with increased oxytocin gene expression in the hypothalamus, although the study used a different model of cirrhosis (33). We did not observe a significant increase in the numbers of oxytocin-positive neurons following BDL in the current study or a previous publication (41). However, we did observe a significant increase in ⌬FosB and oxytocin double labeling in the SON of BDL rats.…”

“…It is also possible that the downstream targets of ⌬FosB are involved in other cellular processes necessary for sustained activation and/or hormone release. It has previously been reported that BDL is associated with significant changes in TRPV2 and TRPV4 expression in SON neurons (11,41). However, few studies have characterized the transcriptional regulation of these channels (13,26,30), and therefore it is not known if their expression is regulated by AP-1 transcription factors.…”

Full-length transient receptor potential vanilloid 1 channels mediate calcium signals and possibly contribute to osmoreception in vasopressin neurones in the rat supraoptic nucleus

“…This is in good agreement with the previous data that Trpv1-4 mRNAs were detected in rat SON neurones that were laser-captured using an anti-AVP antibody [29]. These results are also consistent with our experiments on SON neurones isolated from transgenic rats that revealed that the mannitol response was observed solely in AVP but not in OT neurones.…”

“…It has been demonstrated previously that TRPV1 is expressed in AVP neurones in rat SON [29]. In the present study, we have also found that the distribution of TRPV1 immunoreactivity was confined to the ventral region where most AVP-immunoreactive neurones dwell.…”

ANG II receptor subtype 1a gene knockdown in the subfornical organ prevents increased drinking behavior in bile duct-ligated rats

“…The failure to observe concurrent increases in c-fos and vasopressin hnRNA expression led the authors to suggest the induction of these genes following acute osmotic stimulation likely involves different mechanisms. It is possible that other downstream targets of ⌬FosB, such as transient receptor potential vanilloid channels (14,50) or changes in synaptic function (47,69) are involved in the sustained activation and/or hormone release that results in dilutional hyponatremia.…”