Blunted hypertensive response to Ang II infusion in IFN‐g knockout mice: molecular mechanisms

The hypertensive response to AngII infusion is blunted in CD8−/− and IFNg −/− mice. AIM Determine the molecular basis for the blunted response by evaluating renal Na transporter and SPAK abundance and phosphorylation in IFNg KO vs WT mice using quantitative immunoblots. At baseline, blood pressure (BP) in IFNg KO mice was similar to WT, yet abundance of NKCC2p, NCCp and SPAKp were elevated, evidence for Na transporter activation in the distal nephron. AngII infusion into WT mice raised BP 38 mmHg and increased abundance of NKCC2p, NCCp, SPAK and SPAKp and cleaved form of α ENaC. AngII infusion into IFNg KO raised BP 15 mmHg yet did not change NKCC2p, NCCp, SPAK or SPAKp; however, AngII infusion increased cleaved form of αENaC.WT+AngII vs. WT ‐ baseline IFNg KO vs. WT ‐ baseline IFNg KO+AngII vs. IFNg KONKCC2 0.79 ± 0.03* 1.01 ± 0.09 1.46 ± 0.18 NKCC2p 4.17 ± 0.60* 6.12 ± 1.17* 1.25 ± 0.31 NCC 0.88 ± 0.03 1.28 ± 0.10 1.22 ± 0.09 NCCpS71 8.96 ± 2.53* 8.33 ± 2.55* 1.66 ± 0.40 α‐ENaC (90 kDa) 1.42 ± 0.12* 1.09 ± 0.06 1.54 ± 0.15*α‐ENaC (20 kDa) 2.41 ± 0.12* 1.28 ± 0.1* 1.64 ± 0.25*SPAK 1.41 ± 0.12* 1.28 ± 0.11 1.18 ± 0.10 SPAKp 1.71 ± 0.24* 1.81 ± 0.10* 0.96 ± 0.13In summary, we postulate that IFNg KO mice have a sodium‐losing phenotype that provokes a pronounced activation of NKCC and NCC phosphorylation mediated by SPAK activation, and that the response to AngII infusion is blunted because the AngII targets are already activated . NIH RO1 DK 083785