This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In salt-sensitive subjects, high salt intake results in increased central sympathetic outflow, sodium retention and elevated systemic arterial blood pressure. We demonstrate that central G?i2-subunit proteins mediate the sympathoinhibitory, cardiovascular and renal excretory responses to GPCR activation and are required to attenuate hypertension in salt-resistant subjects. This application will test the overall hypothesis that PVN G?i2-subunit protein-gated pathways play a critical role in the central neural control of sodium and water excretion and systemic arterial blood pressure regulation. Endogenous up-regulation of PVN G?i2 proteins in response to increased salt-intake will potentiate endogenous sympathoinhibitory mechanisms to counter the development of salt-sensitive hypertension whereas failure to endogenously up-regulate PVN G?i2 proteins will exacerbate blood pressure dysregulation. The following Specific Aims will be conducted to test this hypothesis:
Specific Aim 1 : To establish that 1) brain G?i2-subunit protein-gated pathways mediate centrally evoked renal sympathoinhibitory responses to physiological and pharmacological stimuli and, 2) central G?i2-subunit proteins are endogenously up-regulated as a counter regulatory mechanism to attenuate the development of salt-sensitive hypertension in Sprague-Dawley rats.
Specific Aim 2 : To establish the hypothalamic PVN as a specific brain site in which G?i2-subunit proteins are endogenously up-regulated to potentiate renal sympathoinhibitory and natriuretic pathways to maintain fluid and electrolyte homeostasis and counter the development of salt-sensitive hypertension in Sprague-Dawley rats.
Specific Aim 3 : To establish that 1) failure to up-regulate PVN G?i2-subunit proteins, in response to high-salt intake, leads to attenuation of endogenous counter-regulatory renal sympathoinhibitory and natriuretic responses and salt sensitive hypertension in Dahl salt-sensitive rats, and 2) PVN lentiviral overexpression of G?i2-subunit proteins will restore renal sympathoinhibitory and natriuretic mechanisms and attenuate the development of Dahl salt-sensitive hypertension. These innovative studies will further the fields of CNS autonomic regulation and hypertension research potentially indentifying new therapeutic targets for hypertension treatment.
|Li, Li; Bai, Shi; Sheline, Christian T (2017) hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn2+ and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins. Diabetes 66:551-559|
|Hou, Xuwei; Snarski, Patricia; Higashi, Yusuke et al. (2017) Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant-induced cell death. FASEB J 31:3179-3192|
|El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K et al. (2016) Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling. Exp Biol Med (Maywood) 241:539-49|
|Carmichael, C Y; Carmichael, A C T; Kuwabara, J T et al. (2016) Impaired sodium-evoked paraventricular nucleus neuronal activation and blood pressure regulation in conscious Sprague-Dawley rats lacking central G?i2 proteins. Acta Physiol (Oxf) 216:314-29|
|Sukhanov, Sergiy; Snarski, Patricia; Vaughn, Charlotte et al. (2015) Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase. Atherosclerosis 238:313-20|
|Cardenas, Daviel; Carter, Pamela M; Nation, Catherine S et al. (2015) LACK, a RACK1 ortholog, facilitates cytochrome c oxidase subunit expression to promote Leishmania major fitness. Mol Microbiol 96:95-109|
|Breslin, Jerome W; Zhang, Xun E; Worthylake, Rebecca A et al. (2015) Involvement of local lamellipodia in endothelial barrier function. PLoS One 10:e0117970|
|Higashi, Yusuke; Quevedo, Henry C; Tiwari, Summit et al. (2014) Interaction between insulin-like growth factor-1 and atherosclerosis and vascular aging. Front Horm Res 43:107-24|
|El Hajj, Elia C; El Hajj, Milad C; Voloshenyuk, Tetyana G et al. (2014) Alcohol modulation of cardiac matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs favors collagen accumulation. Alcohol Clin Exp Res 38:448-56|
|Blackstock, Christopher D; Higashi, Yusuke; Sukhanov, Sergiy et al. (2014) Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA. J Biol Chem 289:7264-74|
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