Abstract 268: Macrophage Depletion Attenuated Renal Injury and Fibrosis in Angiotensin II Hypertensive Mice

Abstract

Monocyte/macrophage recruitment is closely associated with the degree of hypertensive renal injury. Here we investigated the direct role of macrophage using Liposome encapsulated clodronate (LEC) to deplete monocyte/macrophage in Ang II-induced hypertensive renal injury. C57BL/6 mice were treated with a pressor dose of angiotensin II (Ang, 1.4 mg/kg/day by mini-pump) plus LEC or the PBS-liposome for two weeks. Ang II mice developed hypertension (186 ± 5 vs. 110 ± 4 mmHg in control, p<0.05) , albuminuria (33.9 ± 4.9 vs. 83.6 ± 2.3 μg/mg creatinine in control, p<0.05), glomerulosclerosis and renal fibrosis. LEC reduced Ang II-induced albuminuria (59.6 ± 1.9 μg/mg creatinine, p<0.05) and protected against renal structural injury with a mild reduction in systolic blood pressure (153 ± 3 mmHg, p<0.05). Ang II significantly increased renal macrophage infiltration (MOMA2 + cells) and the protein expression of renal tumor necrosis factor α and interleukin β1, which were significantly reduced in Ang II mice treated with LEC. Ang II increased renal oxidative stress (as demonstrated by increased oxidative fluorescence densities, NADPH oxidative activity and the protein expression of NADPH oxidase subunits gp91phox and p22phox) and the expression of profibrotic factors transform growth factor β1 and fibronectin. Ang II also inhibited the phosphorylation of endothelial nitric oxide synthesis (eNOS, ser1177). LEC revised most of the changes in the Ang II-induced molecules as mentioned above. Our results suggest that renal macrophage is a main mediator to contribute to Ang II-induced hypertensive renal injury and fibrosis, the underlying mechanisms may involve reduction in macrophage-drove renal inflammation and restoration of the balance between renal oxidative stress and eNOS. These findings may lead us to develop a novel therapy directed at targeting the infiltration of macrophages or the macrophages-derived cytokines for treatment of hypertensive renal diseases.