Activity of Protein Kinase C-alpha Within the Subfornical Organ Is Necessary for Fluid Intake in Response to Brain Angiotensin

作者：Coble Jeffrey P; Johnson Ralph F; Cassell Martin D; Johnson Alan Kim; Grobe Justin L; Sigmund Curt D^*

来源：Hypertension, 2014, 64(1): 141-148.

DOI：10.1161/HYPERTENSIONAHA.114.03461

• adenoviridae
• angiotensin-II
• brain
• drinking
• protein kinases

Angiotensin-II production in the subfornical organ acting through angiotensin-II type-1 receptors is necessary for polydipsia, resulting from elevated renin-angiotensin system activity. Protein kinase C and mitogen-activated protein kinase pathways have been shown to mediate effects of angiotensin-II in the brain. We investigated mechanisms that mediate brain angiotensin-II-induced polydipsia. We used double-transgenic sRA mice, consisting of human renin controlled by the neuron-specific synapsin promoter crossed with human angiotensinogen controlled by its endogenous promoter, which results in brain-specific overexpression of angiotensin-II, particularly in the subfornical organ. We also used the deoxycorticosterone acetate-salt model of hypertension, which exhibits polydipsia. Inhibition of protein kinase C, but not extracellular signal-regulated kinases, protein kinase A, or vasopressin V-1A and V-2 receptors, corrected the elevated water intake of sRA mice. Using an isoform selective inhibitor and an adenovirus expressing dominant negative protein kinase C- revealed that protein kinase C- in the subfornical organ was necessary to mediate elevated fluid and sodium intake in sRA mice. Inhibition of protein kinase C activity also attenuated polydipsia in the deoxycorticosterone acetate-salt model. We provide evidence that inducing protein kinase C activity centrally is sufficient to induce water intake in water-replete wild-type mice, and that cell surface localization of protein kinase C- can be induced in cultured cells from the subfornical organ. These experimental findings demonstrate a role for central protein kinase C activity in fluid balance, and further mechanistically demonstrate the importance of protein kinase C- signaling in the subfornical organ in fluid intake stimulated by angiotensin-II in the brain.

• 出版日期2014-7