Most forms of chronic kidney disease culminate in renal fibrosis that heralds organ failure. In contrast to the protective effects of globally blocking type 1 angiotensin (AT(1)) receptors throughout the body, activating AT(1) receptors directly on immune cells may serve protective functions. However, the effects of stimulating the T-cell AT(1) receptor on the progression of renal fibrosis remain unknown. In this study, mice with T-cell-specific deletion of the dominant murine AT(1) receptor isoform Lck-Cre Agtra(flox/flox) [total knockout (TKO)] and wild-type (WT) controls were subjected to the unilateral ureteral obstruction model of kidney fibrosis. Compared with WT controls, obstructed kidneys from TKO mice at day 14 had increased collagen 1 deposition. CD4(+) T cells, CD11b(+)Ly6C(hi) myeloid cells, and mRNA levels of Th1 inflammatory cytokines are elevated in obstructed TKO kidneys, suggesting that augmented Th1 responses in the TKO mice may exaggerate renal fibrosis by driving proinflammatory macrophage differentiation. In turn, T-bet deficient (T-bet knockout) mice lacking Th1 responses have attenuated collagen deposition after unilateral ureteral obstruction. We conclude that activating the AT(1) receptor on T cells mitigates renal fibrogenesis by inhibiting Th1 differentiation and renal accumulation of profibrotic macrophages.
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