Abstract
Previous studies utilizing the SS p67 phox–/– rat have demonstrated the importance of systemic NADPH oxidase NOX2-derived reactive oxygen species (ROS) production in the pathogenesis of Dahl Salt-Sensitive (SS) hypertension and renal damage. Our laboratory has established a key role for renal immune cell infiltration in the development of SS hypertension and observed an enrichment of NOX2 subunits in infiltrating T cells. The contribution of ROS specifically derived from immune cells in SS hypertension remains unknown. To assess the role of ROS in immune cells, SS p67 phox–/– rats underwent total body irradiation and received bone marrow transfer from either SS p67 phox–/– (p67/p67) or SS (p67/SS) donor rats. p67/SS rats would be capable of producing NOX2-derived ROS only in the transferred SS cells of hematopoietic origin while the p67/p67 control group would be unable to produce NOX2-derived ROS globally. Mean arterial pressure (MAP) was not different between the p67/SS and p67/p67 rats when fed a 0.4% NaCl diet (112.6±1.4 vs 110.7±2.4 mmHg, n=4-5). After 3 weeks of high salt, however, there was a significantly greater increase in MAP in the p67/SS rats (176.1±4.7 mmHg) compared to the p67/p67 control rats (147.9±8.4 mmHg), which was accompanied by a significant increase in albuminuria (230.3±13.9 vs 153.1±14.9 mg/day, p67/SS vs p67/p67, n=5-6). Interestingly, upon analysis of the immune cells in the kidney, no differences were detected in the number of CD45+ total leukocytes, CD11b/c+ monocytes/macrophages, CD3+ T cells, and CD45R+ B cells between the p67/SS and p67/p67 (n=4-5), indicating that the recruitment of immune cells into the kidney during hypertension and renal damage is independent of NOX2-derived ROS production from the renal parenchyma. The respiratory burst response to phorbol 12-myristate 13-acetate stimulus (135 μM) in peritoneal macrophages isolated from p67/SS was 4.0-fold greater compared to nonresponsive p67/p67 cells, and was completely inhibited by superoxide dismutase, demonstrating that the reconstituted bone marrow cells in the p67/SS are capable of producing superoxide. In summary, the production of NOX2-derived ROS from immune cells alone is sufficient for the development of Dahl SS hypertension and renal damage.
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