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.
- 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−/− MiceNikhil V. Kamat, Salim R. Thabet, Liang Xiao, Mohamed A. Saleh, Annet Kirabo, Meena S. Madhur, Eric Delpire, David G. Harrison and Alicia A. McDonoughHypertension. 2015;HYPERTENSIONAHA.114.04975, originally published January 19, 2015https://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−/− MiceNikhil V. Kamat, Salim R. Thabet, Liang Xiao, Mohamed A. Saleh, Annet Kirabo, Meena S. Madhur, Eric Delpire, David G. Harrison and Alicia A. McDonoughHypertension. 2015;HYPERTENSIONAHA.114.04975, originally published January 19, 2015https://doi.org/10.1161/HYPERTENSIONAHA.114.04975