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Abstracts
DELETION OF 110-HYDROXYSTEROID DEHYDROGENASE TYPE 2 IN THE NUCLEUS OF THE SOLITARY TRACT CAUSES SALT APPETITE AND HYPERTENSION
Evans, L.C., Holmes, M.C., Mullins, J.J., and Bailey, M.A.
British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
Ablation of the gene encoding 11p-hydroxysteroid dehydrogenase type 2 causes severe hypertension and abnormal renal handling of sodium [1, 2]. Hsd11b2 heterozygote mice have salt-sensitive blood pressure [3], associated with enhanced activity of renal ENaC [4]. Although these studies suggest that renal sodium retention underpins salt-sensitive blood pressure, 1ip-hydroxysteroid dehydrogenase type 2 is also expressed in cardiovascular control centers of the brain. To assess central contributes to salt-sensitivity, Cre-lox technology was used to delete selectively Hsd11b2 in the nucleus of the solitary tract, leaving renal 11 p-hydroxysteroid dehydrogenase type 2 expression unaffected.
Ambulatory blood pressure and renal function were normal but Cre+ mice had an impaired baroreceptor reflex and an innate salt appetite. The hunger for salt was not associated with systemic physiological drivers such as sodium/volume depletion and the increased intake caused a rapid and sustained hypertension. Importantly, matched sodium intake did not increase blood pressure in wild-types. Systemic spironolactone blunted the salt-intake in Cre+ mice.
These studies identify mineralocorticoid receptor activation in the nucleus of the solitary tract as a unifying pathway between sodium intake and blood pressure homeostasis. Targeting of salt appetite is an attractive therapeutic intervention for blood pressure management in cardiovascular disease.
References
1. Bailey, M.A., Paterson, J.M., Hadoke, P.W., Wrobel, N., Bellamy, C.O., Brownstein, D.G., Seckl, J.R., Mullins, J.J. A switch in the mechanism of hypertension in the syndrome of apparent mineralocorticoid excess. J. Am. Soc. Nephrol., 2008, 19, pp. 47-58.
2. Kotelevtsev, Y., Brown, R.W., Fleming, S., Kenyon, C., Edwards, C.R., Seckl, J.R., Mullins, J.J. Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2. J. Clin. Invest, 1999, 103, pp. 683-689.
3. Bailey, M.A., Craigie, E., Livingstone, D.E., Kotelevtsev, Y.V., Al-Dujaili, E.A., Kenyon, C.J., Mullins, J.J. Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure. Hypertension., 2011, 57, pp. 515-520.
4. Craigie, E., Evans, L.C., Mullins, J.J., Bailey, M.A. Failure to downregulate the epithelial sodium channel causes salt sensitivity in Hsd11b2 heterozygote mice. Hypertension, 2012, 60, pp. 684-690.
ACUTE REGULATION OF THE WATER CHANNEL AQUAPORIN-2 BY POSTTRANSLATIONAL MODIFICATION
Fenton, R.A.
Department Biomedicine, InterPrET Center, Aarhus University, Denmark
The vasopressin-regulated water channel aquaporin-2 (AQP2) is expressed in kidney CNT cells, CD principal cells, and inner medullary collecting duct (IMCD) cells. Apical plasma membrane abundance of AQP2 is the rate-limiting step and controls the reabsorption of water; a result of regulated exocytosis of subapical AQP2 bearing vesicles and regulated AQP2 retrieval from the plasma membrane. Together, these two processes carefully balance the levels of apical membrane AQP2. Several of the cellular functions of AQP2 are regulated by posttranslational modifications. In
particular phosphorylation and ubiquitination are mechanisms that regulate AQP2 subcellular sorting and distribution, degradation, and protein interactions. Modifications of AQP2, unlike other channels/transporters, do not appear to affect the transport capacity of the channel. More recent data using AQP2 as a model plasma membrane protein suggests that site specific phosphorylation of AQP2 is able to override the internalization signal mediated by K63-linked polyubiquitination, providing a novel cell biological concept for membrane protein regulation.
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Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24-68
