published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

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Spontaneously hypertensive rats (SHR) are a well accepted model of primary hypertension. Among other features common to human hypertension, these rats exhibit sympathetic hyperactivity. The neurons of the superior mesenteric ganglion (SMG) from SHR display enhanced collateral sprouting, higher firing rates and hyperinnervation of the mesenteric arteries compared to the SMG neurons from age-matched, normotensive Wistar-Kyoto (WKY) rats. Furthermore, SMG neurons in SHR are exposed to different conditions than are SMG neurons from WKY rats, including enhanced oxidative stress, increased afferent stimulation, and an altered hormonal environment. In order to identify proteins with potential involvement in the establishment or maintenance of peripheral sympathetic hyperactivity in SHR, we used proteomic techniques to search for differences in protein expression between the SMG of SHR and the SMG of WKY rats at 16 and 22 weeks of age. We found an upregulation of predominantly fetally expressed T1 domain and haptoglobin and a downregulation of serine protease inhibitor 2.1 in SHR relative to WKY rats at 16 and 22 weeks; Apolipoprotein-A1 was also found to be upregulated in 22 week SHR SMGs compared to age-matched WKY SMGs. These identifications improve our understanding of the ganglionic microenvironment in SHR and represent targets for the development of novel therapies to treat primary hypertension. Hypertension is one of the defining components of the metabolic syndrome, together with insulin resistance, visceral adiposity and hyperlipidemia. Non-alcoholic fatty liver disease (NAFLD) is also a common feature of the metabolic disorder, and thus primary hypertension and NAFLD are common comorbidities. Despite these clinical connections, very little is known about the effects of primary hypertension on hepatic physiology. We used proteomic techniques to search for evidence of significant involvement of the liver in SHR phenotype at the molecular level. We detected changes in the expression of several proteins involved in the regulation of oxidative stress and lipid metabolism which together show that the liver is strongly involved in the pathologies associated with hypertension. Our results suggest several novel mechanisms for the initiation of oxidative stress in SHR which could contribute to new advances in the treatment of metabolic abnormalities associated with hypertension. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2009-10-27 10:11:05.052

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The organic anion transporting polypeptides (OATP/Oatp) are products of the solute carrier organic anion (<i>SLCO/Slco</i>) transporter gene superfamily and constitute a major class of polyspecific membrane solute carriers at the basolateral membrane of hepatocytes.  Alterations in Oatp hepatic drug uptake have the potential to alter the clinical pharmacokinetics, efficacy and safety of a given drug.  Similarly to their regulation of cytochrome P450 enzymes (CYP450) nuclear receptors (NR), such as the pregnane x receptor (PXR) and constitutive androstane receptor (CAR) have been implicated in the transcriptional regulation of Oatps. Dose response experiments were performed using known PXR and CAR activators in male Sprague Dawley rats to ascertain the effects of NR activation on hepatic Oatp expression.  Dexamethasone, pregnenolone-16α-carbonitrile (PCN), 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or Phenobarbital (PB) were administered for 72h and Taqman real time PCR used to quantify transcript levels and Western blots used to quantify transporter proteins.  Only Oatp1a4 displayed responsiveness to NR activation, Oatp1a1 and Oatp1b2 levels are not altered by NR regulation.  Oatp1a4 mRNA and protein levels were only increased by the PXR ligands, dexamethasone and PCN, dexamethasone being the more potent PXR activator compared to PCN.  Dexamethasone resulted in a statistically significant 8-fold induction of Oatp1a4 mRNA with a maximal increase in response occurring at 50mg/kg (12703 ± 1985 copies/ng RNA compared with control 1540 ± 193 copies/ng RNA, p &lt; 0.001). Increasing doss of 100 mg/kg and 150 mg/kg did not result in increased Oatp1a4 levels.  Western blotting showed that dexamethasone and PCN resulted in an increase of Oatp1a4 protein.  The CAR activator, PB, increased Oatp1a4 protein levels; however this is likely to be via a post transcriptional mechanism as there was no concurrent increase in Oatp1a4 mRNA.

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