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Original Article

Renal Transporter Activation During Angiotensin-II Hypertension is Blunted in Interferon-γ−/− and Interleukin-17A−/− Mice

Nikhil V. Kamat, Salim R. Thabet, Liang Xiao, Mohamed A. Saleh, Annet Kirabo, Meena S. Madhur, Eric Delpire, David G. Harrison, Alicia A. McDonough
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https://doi.org/10.1161/HYPERTENSIONAHA.114.04975
Hypertension. 2015;HYPERTENSIONAHA.114.04975
Originally published January 19, 2015
Nikhil V. Kamat
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Salim R. Thabet
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Liang Xiao
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Mohamed A. Saleh
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Annet Kirabo
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Meena S. Madhur
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Eric Delpire
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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David G. Harrison
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Alicia A. McDonough
From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Abstract

Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration, and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically interferon-γ (IFN-γ) and interleukin-17A (IL-17A), to sodium transporter regulation in the kidney during angiotensin-II (Ang-II) hypertension. C57BL/6J (wild-type) mice responded to Ang-II infusion (490 ng/kg per minute, 2 weeks) with a rise in blood pressure (170 mm Hg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ−/−) or IL-17A (IL-17A−/−) exhibited a blunted rise in blood pressure (<150 mm Hg), and both the genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, Ang-II infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter, and Ste20/SPS-1–related proline-alanine–rich kinase, in both the wild-type and the IL-17A−/− but not in IFN-γ−/− mice; epithelial Na channel abundance increased similarly in all the 3 genotypes. In the proximal nephron, Ang-II infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A−/− and IFN-γ−/−, but not in wild-type; the Na-phosphate cotransporter decreased in all the 3 genotypes. Our results suggest that during Ang-II hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.

  • angiotensin-II
  • cytokines
  • epithelial Na+ channel
  • NHE3 protein
  • NKCC2 protein
  • sodium chloride cotransporters
  • SPAK protein
  • Received November 25, 2014.
  • Revision received December 4, 2014.
  • Accepted December 11, 2014.
  • © 2015 American Heart Association, Inc.
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    Renal Transporter Activation During Angiotensin-II Hypertension is Blunted in Interferon-γ−/− and Interleukin-17A−/− Mice
    Nikhil V. Kamat, Salim R. Thabet, Liang Xiao, Mohamed A. Saleh, Annet Kirabo, Meena S. Madhur, Eric Delpire, David G. Harrison and Alicia A. McDonough
    Hypertension. 2015;HYPERTENSIONAHA.114.04975, originally published January 19, 2015
    https://doi.org/10.1161/HYPERTENSIONAHA.114.04975

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    Renal Transporter Activation During Angiotensin-II Hypertension is Blunted in Interferon-γ−/− and Interleukin-17A−/− Mice
    Nikhil V. Kamat, Salim R. Thabet, Liang Xiao, Mohamed A. Saleh, Annet Kirabo, Meena S. Madhur, Eric Delpire, David G. Harrison and Alicia A. McDonough
    Hypertension. 2015;HYPERTENSIONAHA.114.04975, originally published January 19, 2015
    https://doi.org/10.1161/HYPERTENSIONAHA.114.04975
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