Abstract 2530: Modulation of Renal Medullary Superoxide, Natriuresis and Diuresis by Lymphocytes
Angiotensin (Ang) II increases production of superoxide by the NADPH oxidase in the renal medulla, which in turn can reduce medullary blood flow, inducing water and salt retention and promoting hypertension. We recently observed that mice lacking T and B cells (RAG-1c) have blunted hypertension during Ang II infusion and do not develop abnormalities of vascular function. Adoptive transfer of T but not B cells completely restored these abnormalities. Accordingly we investigated the role of T cells in regulation of renal superoxide production, diuresis and natriuresis. The increase in blood pressure caused by two weeks of Ang II infusion (500ng/kg/min), as measured by tail cuff, was markedly reduced in RAG-1-/- vs. WT animals (14±5 vs. 163±5 mmHg; P<0.02). Ang II also caused a greater diuresis (2.9±0.3 vs. 1.6±0.2 ml/day; P<0.01) and natriuresis (0.25±0.05 vs. 0.12±0.03 mEq/day; P<0.01) in RAG-1-/- vs WT mice. Water intake did not differ between the groups (5.7±1.0 vs. 5.2±1.0 ml/day; P<0.6). The increase in renal medullary superoxide caused by Ang II was plunted in RAG-1-/- (3.6±0.6 vs. 5.5±0.8 AU Oxyethidium/protein; P<0.05) as shown by HPLC and confirmed by oxidative fluorescent microphotography. Additionally Ang II treated WT mice showed a trend for an increase in renal infiltration of CD4+CD8+T cells and also CD3+CD4-CD8-cells as shown by FACS analysis of cell suspensions from collagenase digested kidneys. Ang II also increased T cell levels of the TH1 cytokine TNF-alpha in WT animals. We hypothesize that Ang II activates T cells which release cytokines that stimulate superoxide production in the kidney leading to medullary vasoconstriction, sodium retention and hypertension. These findings provide a new mechanism underlying hypertension involving T cell interaction with the renal medulla.