Exacerbation of Dahl SS Hypertension and Renal Damage by NOX2 in CD4+ T Cells.

Abstract

BACKGROUND Infiltration of T cells into the kidney of Dahl salt-sensitive (SS) rats accompanies SS hypertension and renal damage. Genetic deletion of T cells on the SS background (knockout of the CD247 gene in Dahl salt-sensitive rat [SSCD247-/-]) attenuates hypertension and renal damage, and adoptive transfer of T cells restores the disease phenotype in an NOX2 (NADPH oxidase 2)-dependent manner. This study aimed to identify the specific T-cell subtype involved in the amplification of Dahl SS hypertension. METHODS Adoptive transfer of purified CD (cluster of differentiation) 4+ or CD8+ T cells isolated from SS rats or from rats with a genetic deletion of a subunit of NOX2 was performed into the SSCD247-/-. A negative control group received PBS vehicle. After 3 weeks of a high-salt (4.0% NaCl) diet, rats receiving CD4+ T cells from the SS demonstrated amplified SS hypertension and albuminuria compared with all other groups, including the rats that received CD4+ T cells lacking functional NOX2. RESULTS No differences were observed in rats receiving CD8+ T cells. Flow cytometric analysis documented equal reconstitution of CD3+ cells in the adoptive transfer rats. A gene expression analysis demonstrated upregulation of inflammatory genes in the CD4+ cells in the kidney of the SS rats compared with the T cells of rats lacking functional NOX2. Subsequent experiments documented a positive correlation between CD4+ T cells in diseased human kidneys and renal damage, providing a translational aspect to this study. CONCLUSIONS In summary, these studies indicate that CD4+ T cells amplify SS hypertension and renal damage in the Dahl SS rats via an NOX2-dependent mechanism.