An essential role of angiotensin II receptor type 1a in recipient kidney, not in transplanted peripheral blood leukocytes, in progressive immune-mediated renal injury.

ABSTRACT

Despite an intensive effort of elucidating the pathogenic role of angiotensin II (AII) in immune-mediated renal injury, the precise mechanisms are poorly understood. In the present study, we examined the site of AII action, peripheral blood leukocytes or resident renal cells, in immune-mediated renal injury using AII type 1a receptor (AT1a)-deficient homozygous (AT1a -/-) mice and wild-type (AT1a +/+) mice. The AT1a -/- mice showed delayed-type hypersensitivity similar to that of the AT1a +/+ mice, suggesting that the lack of AT1a does not impair a Th1-type cellular immune response of peripheral blood leukocytes involved in immune-mediated renal injury. We then generated the radiation bone marrow chimera mice, WA and AW, which have transplanted peripheral blood leukocytes from the AT1a +/+ and AT1a -/- mice into the AT1a -/- and AT1a +/+ mice, respectively. As controls, WW and AA, the AT1a +/+ and AT1a -/- mice given bone marrow cells from the AT1a +/+ and AT1a -/- mice, respectively, were generated. Seven days after induction of antiglomerular basement membrane nephritis, glomerulosclerosis observed in the WW mice was markedly ameliorated in the WA mice, but not in the AW mice. In addition, the recruitment of monocytes/macrophages and the expressions of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in the glomeruli of the AW and WW mice was evident, but such significant phenotypes were not seen in the WA and AA mice, showing a marked amelioration of renal injury dependent on the host AT1a genotype. These results demonstrate an essential role of AT1a in intrinsic renal cells for progressive immune-mediated renal injury and indicate a beneficial effect of blocking the renin-angiotensin system in the treatment of such diseases.