Endothelin-1 as a master regulator of whole-body Na+ homeostasis.
The current study was designed to determine whether vascular endothelial-derived endothelin-1 (ET-1) is important for skin Na(+) buffering. In control mice (C57BL/6J), plasma Na(+) and osmolarity were significantly elevated in animals on high- vs. low-salt (HS and LS, respectively) intake. The increased plasma Na(+) and osmolarity were associated with increased ET-1 mRNA in vascular tissue. There was no detectable difference in skin Na(+):H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na(+):H2O was significantly increased by blockade of the endothelin type A receptor with ABT-627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half-maximal inhibitory concentration, 0.055 nM). ET-1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9 pg/mg vs. 106.4 ± 6.8 pg/mg; P < 0.05), but not in vascular endothelial cell endothelin-1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na(+):H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET-1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET-1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na(+).
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Joshua S
JS
Speed
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
J Brett
JB
Heimlich
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Kelly A
KA
Hyndman
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Brandon M
BM
Fox
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Vivek
V
Patel
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Masashi
M
Yanagisawa
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Jennifer S
JS
Pollock
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Jens M
JM
Titze
*Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Physiology, Georgia Regents University, Augusta, Georgia, USA; Center for Behavioral Molecular Genetics, University of Tsukuba, Tsukuba, Japan; and Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA dpollock@uab.edu.
David M
DM
Pollock
D000818:Animals; D019332:Endothelin-1 / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009994:Osmolar Concentration; D012964:Sodium / Q000502:physiology*; D012982:Sodium, Dietary / Q000008:administration & dosage
D019332:Endothelin-1; D012982:Sodium, Dietary; D012964:Sodium
endothelium; inflammation; skin; vascular