title: Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice.
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.
authors.affiliation: 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.).
authors.forename: Nikhil V
authors.initials: NV
authors.lastname: Kamat
authors.affiliation: 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.).
authors.forename: Salim R
authors.initials: SR
authors.lastname: Thabet
authors.affiliation: 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.).
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.affiliation: 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.).
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: 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.).
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.affiliation: 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.).
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.affiliation: 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.).
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.affiliation: 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.).
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.affiliation: 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.). mcdonoug@usc.edu.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005838:Genotype; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012964:Sodium / Q000378:metabolism*; D049992:Sodium Chloride Symporters / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D020381:Interleukin-17; C000613386:Slc9a3 protein, mouse; D049992:Sodium Chloride Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D064466:Solute Carrier Family 12, Member 1; D000804:Angiotensin II; D007371:Interferon-gamma; D012964:Sodium
keywords: NHE3 protein; NKCC2 protein sodium chloride cotransporters; SPAK protein; angiotensin-II; cytokines; epithelial Na+ channel