CD4+ T cells amplify hypertension and renal damage in the Dahl SS through an NADPH Oxidase 2 (NOX2)-dependent process
Authors: Walton Samuel , Dasinger John Henry , Cherian-Shaw Mary , Burns Emily , Abais-Battad Justine , Mattson David 
Published: May 2023

Infiltration of T cells into the kidney of the Dahl Salt Sensitive (SS), a rat model of human disease, accompanies the development of salt-sensitive hypertension and renal damage. Deletion of T cells on the Dahl SS genetic background (SSCD247-/-) attenuates the hypertension and renal damage, and subsequent replacement of T cells by splenocyte transfer restores the disease phenotype. These studies demonstrate a role for T cells to amplify salt-sensitive hypertension, but the T cell subtype and the mechanism of action are not understood. A potential mechanism of T cell action is free radical production since the deletion of the p67phox subunit of NADPH oxidase 2 (NOX2) in adoptively transferred splenocytes attenuates Dahl SS hypertension and kidney damage. The present study was therefore performed to test the hypothesis that NOX2 in CD4+ T cells amplifies the SS phenotype and associated renal damage in the Dahl SS. We tested this hypothesis by adoptively transferring CD4+ T cells (~5 million) from splenocytes isolated from the Dahl SS (SS→CD247), from SS rats lacking p67phox (SSp67phox-/-), a critical subunit of NOX2 (p67phox→CD247), or PBS (PBS→CD247) into the SSCD247-/- rat on postnatal day 5. Animals were instrumented with radiotelemeters at 7 weeks of age. After a week of recovery, baseline measurements of blood pressure and albumin excretion were obtained while they were maintained on a low salt (LS, 0.4% NaCl) diet. Rats were then switched to a high salt (HS, 4.0% NaCl) diet for 21 days, with continuous blood pressure measurements and urine collections every 7 days. On day 22, the rats were euthanized, and their kidneys were perfused and collected for histology and renal immune cell characterization through flow cytometry. During the baseline period there was no significant difference in mean arterial pressure (MAP) between the SS→CD247, p67phox→CD247, and PBS→CD247 groups (112±1, 108±2, 109±2 mmHg; n=8,7,7, respectively). After 20 days on a high salt challenge there was a significant difference in MAP between the SS→CD247 (149±4 mmHg, n=8) and the p67phox→CD247 (133±2 mmHg, n=7, p<0.05) but no significant difference between the p67phox→CD247 MAP and the PBS→CD247 group (132±5 mmHg, n=7). Albuminuria trended higher in the SS→CD247 (172±22 mg/day) when compared to p67phox→CD247 (153±10 mg/day) and PBS→CD247 (143±44 mg/day) but did not reach significance. Data collected from the flow analysis confirmed the absence of CD3+ T cells in the PBS→CD247 and demonstrated no difference in the number of CD4+ T cells that infiltrated the kidneys between the SS→CD247 and the p67phox→CD247. These results indicate that ROS production from CD4+ T cells significantly amplifies the salt sensitive hypertension and renal HL161231, Georgia Research Alliance This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.