27 research outputs found
High salt diet impairs cerebral blood flow regulation via saltâinduced angiotensin II suppression
ObjectivesThis study sought to determine whether saltâinduced ANG II suppression contributes to impaired CBF autoregulation.MethodsCerebral autoregulation was evaluated with LDF during graded reductions of blood pressure. Autoregulatory responses in rats fed HS (4% NaCl) diet vs LS (0.4% NaCl) diet were analyzed using linear regression analysis, modelâfree analysis, and a mechanistic theoretical model of blood flow through cerebral arterioles.ResultsAutoregulation was intact in LSâfed animals as MAP was reduced via graded hemorrhage to approximately 50Â mm Hg. Shortâterm (3Â days) and chronic (4Â weeks) HS diet impaired CBF autoregulation, as evidenced by progressive reductions of laser Doppler flux with arterial pressure reduction. Chronic low dose ANG II infusion (5Â mg/kg/min, i.v.) restored CBF autoregulation between the preâhemorrhage MAP and 50Â mm Hg in rats fed shortâterm HS diet. Mechanisticâbased model analysis showed a reduced myogenic response and reduced baseline VSM tone with shortâterm HS diet, which was restored by ANG II infusion.ConclusionsShortâterm and chronic HS diet lead to impaired autoregulation in the cerebral circulation, with saltâinduced ANG II suppression as a major factor in the initiation of impaired CBF regulation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149286/1/micc12518_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149286/2/micc12518.pd
Type III Nrg1 Back Signaling Enhances Functional TRPV1 along Sensory Axons Contributing to Basal and Inflammatory Thermal Pain Sensation
Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs) [1]. Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons [2]. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions [3]. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K [4], [5], [6], making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function
Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity
Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type IâIV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (Ï2=7.815; P=0.05). The average nucleotide diversity (Ξ=10.0 Ă 10â4) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (Ξ(case)=13.2 Ă 10â4; Ξ(control)=10.0 Ă 10â4). The specific HapICE risk haplotype was associated with increased type III mRNA (F=3.76, P=0.028), which in turn, was correlated with an earlier age of onset (r=â0.343, P=0.038). We found a novel intronic five-SNP haplotype âŒ730âkb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia