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Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of
Hongwei Li1, Yongxin Gao, Carlos Diez Freire
1Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0274, USA.
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.
Insights
Macrophage migration inhibitory factor (MIF) regulates central blood pressure and drinking responses mediated by angiotensin II (ANG II). MIF
Area of Science:
- Neuroendocrinology
- Cardiovascular Physiology
- Molecular Biology
Background:
- Macrophage migration inhibitory factor (MIF) has intracellular roles counteracting angiotensin II (ANG II) effects.
- The paraventricular nucleus (PVN) is crucial for central nervous system (CNS) regulation of cardiovascular function and water intake by ANG II.
Purpose of the Study:
- To investigate the in vivo role of MIF in the PVN in regulating ANG II-mediated cardiovascular and dipsogenic effects.
- To elucidate the mechanism of MIF action in the PVN, specifically its thiol-protein oxidoreductase (TPOR) activity.
Main Methods:
- Intracerebroventricular (icv) injection of ANG II in normotensive rats.
- Administration of AT1-R antagonist losartan in the PVN.
- Adenovirus-mediated MIF gene transfer (Ad-Syn-MIF) to overexpress MIF in PVN neurons.
- Intracellular application of MIF and its TPOR-active fragment (MIF-(50-65)) into PVN neurons.
Main Results:
- ANG II injection increased MIF protein in the PVN, causing pressor and drinking responses.
- These ANG II effects were blocked by losartan and attenuated by MIF overexpression in the PVN.
- Intracellular MIF or MIF-(50-65) application inhibited ANG II's electrophysiological actions in PVN neurons.
Conclusions:
- MIF acts intracellularly within the PVN to regulate central cardiovascular and dipsogenic effects of ANG II.
- The thiol-protein oxidoreductase (TPOR) activity of MIF is essential for its regulatory function in the PVN.
- This study identifies MIF as a key intracellular regulator in the central control of blood pressure and water homeostasis.
