Human clinical trials using type 1 angiotensin (AT₁) 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 AT₁ receptors may have divergent effects on target organ damage in hypertension.

We examined the role of AT₁ receptors on T lymphocytes in the pathogenesis of hypertension and its complications.

Deficiency of AT₁ 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 AT₁ receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT₁ 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.

The current studies identify an unexpected role for AT₁ receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4⁺ T helper cell differentiation.