Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice

Hypertension. 2015 Mar;65(3):569-76. doi: 10.1161/HYPERTENSIONAHA.114.04975. Epub 2015 Jan 19.


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.

Keywords: NHE3 protein; NKCC2 protein sodium chloride cotransporters; SPAK protein; angiotensin-II; cytokines; epithelial Na+ channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / adverse effects*
  • Angiotensin II / pharmacology
  • Animals
  • Biological Transport / physiology
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Disease Models, Animal
  • Epithelial Sodium Channels / metabolism
  • Genotype
  • Hypertension / chemically induced*
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Interferon-gamma / deficiency*
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-17 / deficiency*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Kidney Tubules, Proximal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Sodium / metabolism*
  • Sodium Chloride Symporters / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism
  • Solute Carrier Family 12, Member 1 / metabolism


  • Epithelial Sodium Channels
  • Interleukin-17
  • Slc9a3 protein, mouse
  • Sodium Chloride Symporters
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Solute Carrier Family 12, Member 1
  • Angiotensin II
  • Interferon-gamma
  • Sodium