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Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of angiotensin II

Hongwei Li^*, Yongxin Gao^*, Carlos Diez Freire^*, Mohan K. Raizada^*, Glenn M. Toney and Colin Sumners^*,1

^* Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, Florida, USA; and

Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

¹Correspondence: Department of Physiology and Functional Genomics, College of Medicine, Box 100274, 1600 SW Archer Rd., University of Florida, Gainesville, FL 32610-0274, USA. E-mail: csumners{at}phys.med.ufl.edu

ABSTRACT

Macrophage migration inhibitory factor (MIF) acts intracellularly to counteract the angiotensin (ANG) II type 1 receptor (AT1-R)-mediated chronotropic effect of ANG II in hypothalamic neurons, an effect mediated by the thiol-protein oxidoreductase (TPOR) activity of the MIF molecule. Here we determined the in vivo actions of MIF in regulating the physiological actions of ANG II that are mediated via the paraventricular nucleus (PVN), an area that serves as a relay point in the central nervous system (CNS)-mediated effects of ANG II on cardiovascular functions and water intake. Intracerebroventricular (icv) injection of ANG II into normotensive rats selectively increased MIF protein levels in the PVN and produced significant pressor and drinking responses that were inhibited by PVN administration of the AT1-R antagonist losartan. Overexpression of MIF in PVN neurons via Ad-Syn-MIF gene transfer attenuated the pressor and drinking responses produced by icv-injected ANG II. Consistently, intracellular application of MIF or MIF-(50–65) (which harbors the TPOR activity of MIF) into PVN sympathetic regulatory neurons, blunted the electrophysiological actions of ANG II at these cells. These observations establish for the first time that MIF within the PVN, acting via TPOR, is an intracellular regulator of the central cardiovascular and dipsogenic effects of ANG II.—Li, H., Gao, Y., Freire, C. D., Raizada, M. K., Toney, G. M., Sumners, C. Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of angiotensin II

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