Recent studies in humans and rats suggested that increased Na+ storage in the skin without parallel water retention may predispose to salt-sensitive hypertension. In the current studies, we compared tissue Na+ storage in salt sensitive spontaneously hypertensive rats (SHR) versus salt resistant normotensive Brown Norway (BN-Lx) rats. After salt loading (10 days drinking 1% NaCl solution), the SHR showed significant parallel increase in Na+-to-water as well as (Na++K+)-to-water ratios suggesting increased storage of osmotically inactive Na+ in the skin while no significant changes in skin electrolyte concentrations were observed in BN-Lx rats. SHR rats after salt treatment exhibited a nonsignificant decrease in skin blood capillary number (rarefaction) while BN-Lx rats showed significantly increased skin blood capillary density. Analysis of dermal gene expression profiles in BN-Lx rats after salt treatment showed significant up-regulation of genes involved in angiogenesis and proliferation of endothelial cells contrary to the SHR. Since the skin harbors most of the body's resistance vessels it is possible that blood capillary rarefaction may lead to increased peripheral resistance and salt sensitivity in the SHR.

Department of Pathology 3rd Faculty of Medicine Charles University 10000 Prague Czech Republic

Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University General University Hospital 12800 Prague Czech Republic

Institute of Physiology Czech Academy of Sciences 14220 Prague Czech Republic

Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics Czech Academy of Sciences 14220 Prague Czech Republic

Zobrazit více v PubMed

Weinberger M.H. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481–490. doi: 10.1161/01.HYP.27.3.481. PubMed DOI

Kotchen T.A., Allen W., Cowley A.W., Jr., Frohlich E.D. Salt in health and disease—A delicate balance. N. Engl. J. Med. 2016;68:1229–1237. doi: 10.1056/NEJMra1212606. PubMed DOI

Barba G., Galletti F., Cappuccio F.P., Siani A., Venezia A., Versiero M., Della Valle E., Sorrentino P., Tarantino G., Farinaro E., et al. Incidence of hypertension in individuals with different blood pressure salt-sensitivity: Results of a 15-year follow-up study. J. Hypertens. 2007;25:1465–1471. doi: 10.1097/HJH.0b013e3281139ebd. PubMed DOI

Titze J., Rittweger J., Dietsch P., Krause H., Schwind K.H., Engelke K., Lang R., Kirsch K.A., Luft F.C., Hilgers K.F. Hypertension, sodium retention, calcium excretion and osteopenia in Dahl rats. J. Hypertens. 2004;22:803–810. doi: 10.1097/00004872-200404000-00024. PubMed DOI

Kopp C., Linz P., Dahlmann A., Hammon M., Jantsch J., Müller D.N., Schmieder R.E., Cavallaro A., Eckardt K.U., Uder M., et al. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2013;61:635–640. doi: 10.1161/HYPERTENSIONAHA.111.00566. PubMed DOI

Titze J., Dahlmann A., Lerchl K., Kopp C., Rakova N., Schröder A., Luft F.C. Spooky sodium balance. Kidney Int. 2014;85:759–767. doi: 10.1038/ki.2013.367. PubMed DOI

Prasad A., Dunnill G.S., Mortimer P.S., MacGregor G.A. Capillary rarefaction in the forearm skin in essential hypertension. J. Hypertens. 1995;13:265–268. doi: 10.1097/00004872-199502000-00015. PubMed DOI

Antonios T.F., Singer D.R., Markandu N.D., Mortimer P.S., MacGregor G.A. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension. 1999;34:655–658. doi: 10.1161/01.HYP.34.4.655. PubMed DOI

Antonios T.F., Rattray F.M., Singer D.R., Markandu N.D., Mortimer P.S., MacGregor G.A. Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension. Heart. 2003;89:175–178. doi: 10.1136/heart.89.2.175. PubMed DOI PMC

He F.J., Marciniak M., Markandu N.D., Antonios T.F., MacGregor G.A. Effect of modest salt reduction on skin capillary rarefaction in white, black, and Asian individuals with mild hypertension. Hypertension. 2010;56:253–259. doi: 10.1161/HYPERTENSIONAHA.110.155747. PubMed DOI

Churchill P.C., Churchill M.C., Bidani A.K., Griffin K.A., Picken M., Pravenec M., Kren V., St Lezin E., Wang J.M., Wang N., et al. Genetic susceptibility to hypertension-induced renal damage in the rat. Evidence based on kidney-specific genome transfer. J. Clin. Investig. 1997;100:1373–1382. doi: 10.1172/JCI119657. PubMed DOI PMC

Liška F., Mancini M., Krupková M., Chylíková B., Křenová D., Šeda O., Šilhavý J., Mlejnek P., Landa V., Zídek V., et al. Plzf as a candidate gene predisposing the spontaneously hypertensive rat to hypertension, left ventricular hypertrophy, and interstitial fibrosis. Am. J. Hypertens. 2014;27:99–106. doi: 10.1093/ajh/hpt156. PubMed DOI

Liška F., Landa V., Zídek V., Mlejnek P., Šilhavý J., Šimáková M., Strnad H., Trnovská J., Škop V., Kazdová L., et al. Downregulation of Plzf gene ameliorates metabolic and cardiac traits in the spontaneously hypertensive rat. Hypertension. 2017;69:1084–1091. doi: 10.1161/HYPERTENSIONAHA.116.08798. PubMed DOI

Lunova M., Kubovciak J., Smolková B., Uzhytchak M., Michalova K., Dejneka A., Strnad P., Lunov O., Jirsa M. Expression of interferons lambda 3 and 4 induces identical response in human liver cell lines depending exclusively on canonical signaling. Int. J. Mol. Sci. 2021;22:2560. doi: 10.3390/ijms22052560. PubMed DOI PMC

Rossitto G., Mary S., Chen J.Y., Boder P., Chew K.S., Neves K.B., Alves R.L., Montezano A.C., Welsh P., Petrie M.C., et al. Tissue sodium excess is not hypertonic and reflects extracellular volume expansion. Nat. Commun. 2020;11:4222. doi: 10.1038/s41467-020-17820-2. PubMed DOI PMC

Titze J., Lang R., Ilies C., Schwind K.H., Kirsch K.A., Dietsch P., Luft F., Hilgers K.F. Osmotically inactive skin Na+ storage in rats. Am. J. Physiol. Ren. Physiol. 2003;285:F1108–F1117. doi: 10.1152/ajprenal.00200.2003. PubMed DOI

Titze J., Bauer K., Schafflhuber M., Dietsch P., Lang R., Schwind K.H., Luft F.C., Eckardt K.-U., Hilgers K.F. Internal sodium balance in DOCA-salt rats: A body composition study. Am. J. Physiol. Ren. Physiol. 2005;289:F793–F802. doi: 10.1152/ajprenal.00096.2005. PubMed DOI

Chrysant S.G., Walsh G.M., Kem D.C., Frohlich E.D. Hemodynamic and metabolic evidence of salt sensitivity in spontaneously hypertensive rats. Kidney Int. 1979;15:33–37. doi: 10.1038/ki.1979.4. PubMed DOI

Flynn F.W., Culver B., Newton S.V. Salt intake by normotensive and spontaneously hypertensive rats: Two-bottle and lick rate analyses. Physiol. Behav. 2003;78:689–696. doi: 10.1016/S0031-9384(03)00062-3. PubMed DOI

McConnell S.D., Henkin R.I. Na,Cl preference in spontaneously hypertensive rats; age and blood pressure effects. Am. J. Physiol. 1973;225:624–627. doi: 10.1152/ajplegacy.1973.225.3.624. PubMed DOI

Di Nicolantonio R., Kren V., Zidek V., Pravenec M. Salt preference of congenic strains derived from the spontaneously hypertensive rat. Physiol. Behav. 2004;80:617–622. doi: 10.1016/j.physbeh.2003.11.001. PubMed DOI

Hansen-Smith F.M., Morris L.W., Greene A.S., Lombard J.H. Rapid microvessel rarefaction with elevated salt intake and reduced renal mass hypertension in rats. Circ. Res. 1996;79:324–330. doi: 10.1161/01.RES.79.2.324. PubMed DOI

Greene A.S., Tonellato P.J., Lui J., Lombard J.H., Cowley A.W., Jr. Microvascular rarefaction and tissue vascular resistance in hypertension. Pt 2Am. J. Physiol. 1989;256:H126–H131. doi: 10.1152/ajpheart.1989.256.1.H126. PubMed DOI

Greene A.S., Lombard J.H., Cowley A.W., Jr., Hansen-Smith F.M. Microvessel changes in hypertension measured by Griffonia simplicifolia I lectin. Pt 2Hypertension. 1990;15:779–783. doi: 10.1161/01.HYP.15.6.779. PubMed DOI

Triantafyllou A., Anyfanti P., Pyrpasopoulou A., Triantafyllou G., Aslanidis S., Douma S. Capillary rarefaction as an index for the microvascular assessment of hypertensive patients. Curr. Hypertens. Rep. 2015;17:33. doi: 10.1007/s11906-015-0543-3. PubMed DOI

Markiewski M.M., Daugherity E., Reese B., Karbowniczek M. The role of complement in angiogenesis. Antibodies. 2020;9:67. doi: 10.3390/antib9040067. PubMed DOI PMC

Silverman G.A., Whisstock J.C., Bottomley S.P., Huntington J.A., Kaiserman D., Luke C.J., Pak S.C., Reichhart J.-M., Bird P.I. Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems. J. Biol. Chem. 2010;285:24299–24305. doi: 10.1074/jbc.R110.112771. PubMed DOI PMC

Juráňová J., Franková J., Ulrichová J. The role of keratinocytes in inflammation. J. Appl. Biomed. 2017;15:169–179. doi: 10.1016/j.jab.2017.05.003. DOI

Sivaprasad U., Kinker K.G., Ericksen M.B., Lindsey M., Gibson A.M., Bass S.A., Hershey N.S., Deng J., Medvedovic M., Hershey G.K.K. SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis. J. Investig. Derm. 2015;135:160–169. doi: 10.1038/jid.2014.353. PubMed DOI PMC

Machnik A., Neuhofer W., Jantsch J., Dahlmann A., Tammela T., Machura K., Park J.K., Beck F.X., Müller D.N., Derer W., et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat. Med. 2009;15:545–552. doi: 10.1038/nm.1960. PubMed DOI

Machnik A., Dahlmann A., Kopp C., Goss J., Wagner H., van Rooijen N., Eckardt K.U., Müller D.N., Park J.K., Luft F.C., et al. Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats. Hypertension. 2010;55:755–761. doi: 10.1161/HYPERTENSIONAHA.109.143339. PubMed DOI

Wiig H., Schröder A., Neuhofer W., Jantsch J., Kopp C., Karlsen T.V., Boschmann M., Goss J., Bry M., Rakova N., et al. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J. Clin. Investig. 2013;123:2803–2815. doi: 10.1172/JCI60113. PubMed DOI PMC

Rendell M.S., Finnegan M.F., Healy J.C., Lind A., Milliken B.K., Finney D.E., Bonner R.F. The relationship of laser-Doppler skin blood flow measurements to the cutaneous microvascular anatomy. Microvasc. Res. 1998;55:3–13. doi: 10.1006/mvre.1997.2049. PubMed DOI

Pravenec M., Klír P., Kren V., Zicha J., Kunes J. An analysis of spontaneous hypertension in spontaneously hypertensive rats by means of new recombinant inbred strains. J. Hypertens. 1989;7:217–221. doi: 10.1097/00004872-198903000-00008. PubMed DOI

Kurtz T.W., DiCarlo S.E., Pravenec M., Schmidlin O., Tanaka M., Morris R.C., Jr. An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension. Kidney Int. 2016;90:965–973. doi: 10.1016/j.kint.2016.05.032. PubMed DOI PMC

Kurtz T.W., Dicarlo S.E., Pravenec M., Morris R.C., Jr. The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension. Curr. Opin. Nephrol. Hypertens. 2018;27:83–92. doi: 10.1097/MNH.0000000000000394. PubMed DOI