A Novel Role for Type 1 Angiotensin Receptors on T Lymphocytes to Limit Target Organ Damage in Hypertension

Rationale: Human clinical trials using type 1 angiotensin (AT(1)) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT(1) receptors may have divergent effects on target organ damage in hypertension. Objective: We examined the role of AT(1) receptors on T lymphocytes in the pathogenesis of hypertension and its complications. Methods and Results: Deficiency of AT(1) receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4(+) T cells from T cell knockout mice lacking AT(1) receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-gamma and tumor necrosis factor-alpha. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT(1) receptor-deficient CD4(+) T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. Conclusions: The current studies identify an unexpected role for AT(1) receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4(+) T helper cell differentiation. (Circ Res. 2012;110:1604-1617.)