CD247 modulates blood pressure by altering t-lymphocyte infiltration in the kidney

The CD3 ζ chain (CD247), a gene involved in T-cell signaling, has been shown to associate with blood pressure in human genetic studies. To test the functional role of CD247 in hypertension and renal disease, zinc-finger nucleases targeting CD247 were injected into Dahl salt-sensitive (SS/JrHsdMcwi) embryos. The resulting 11-bp frameshift deletion in exon 1 of CD247 led to a predicted premature stop codon. Western blotting confirmed the absence of CD247 protein in the thymus, and flow cytometry (n=5-9 per group) demonstrated that the mutant rats (CD247) have a >99% reduction in circulating CD3 T cells compared with littermate controls (CD247). Studies were performed on age-matched, littermate male, CD247 and CD247 rats fed a 4.0% NaCl diet for 3 weeks. The infiltration of CD3 T cells into the kidney after high salt was significantly blunted in CD247 (1.4±0.4×10 cells per kidney) when compared with that in the CD247 (8.7±2.0×10 cells per kidney). Accompanying the reduced infiltration of T cells, mean arterial blood pressure was significantly lower in CD247 than in CD247 (134±1 versus 151±2 mm Hg). As an index of kidney disease, urinary albumin and protein excretion rates were significantly reduced in CD247 (17±1 and 62±2 mg/d, respectively) when compared with that in CD247 (49±3 and 121±5 mg/d, respectively). Glomerular and renal tubular damage were also attenuated in the CD247. These studies demonstrate that functional T cells are required for the full development of Dahl salt-sensitive hypertension and indicate that the association between CD247 and hypertension in humans may be related to altered immune cell function.