title: CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney.
abstract: 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(5) cells per kidney) when compared with that in the CD247(+/+) (8.7±2.0×10(5) 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.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. dmattson@mcw.edu.
authors.forename: Nathan
authors.initials: N
authors.lastname: Rudemiller
authors.forename: Hayley
authors.initials: H
authors.lastname: Lund
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.forename: David L
authors.initials: DL
authors.lastname: Mattson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017252:CD3 Complex / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007111:Immunity, Cellular / Q000235:genetics*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D012313:RNA / Q000235:genetics*; D051381:Rats; D020303:Rats, Inbred Dahl; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D012313:RNA
keywords: hypertension; immune system; kidney; lymphocytes; rats