Abstract
Monocyte/macrophage recruitment is closely associated with the degree of hypertensive renal injury. We investigated the direct role of macrophages using liposome-encapsulated clodronate (LEC) to deplete monocytes/macrophages in hypertensive renal injury. C57BL/6 mice were treated with a pressor dose of angiotensin (Ang, 1.4 mg/kg/day) II plus LEC or the PBS-liposome for 2 weeks. Ang II mice developed hypertension, albuminuria, glomerulosclerosis, and renal fibrosis. LEC treatment reduced systolic blood pressure (SBP), albuminuria, and protected against renal structural injury in Ang II mice. Ang II significantly increased renal macrophage infiltration (MOMA2+ cells) and the expression of renal tumor necrosis factor α and interleukin β1, which were significantly reduced in Ang II/LEC mice. Ang II increased renal oxidative stress and the expression of profibrotic factors transforming growth factor (TGF) β1 and fibronectin. Ang II also inhibited the phosphorylation of endothelial nitric oxide synthase [phospho-endothelial nitric oxide synthesis (eNOS), ser1177]. LEC treatment reduced renal oxidative stress and TGFβ1 and fibronectin expressions, and increased phospho-eNOS expression in the Ang II mice. In Dahl rats of salt-sensitive hypertension, LEC treatment for 4 weeks significantly attenuated the elevation of SBP induced by high salt intake and protected against renal injury and fibrosis. Our results demonstrate that renal macrophages play a critical role in the development of hypertension and hypertensive renal injury and fibrosis; the underlying mechanisms may be involved in the reduction in macrophage-driven renal inflammation and restoration of the balance between renal oxidative stress and eNOS. Therefore, macrophages should be considered as a potential therapeutic target to reduce the adverse consequences of hypertensive renal diseases.
Highlights
Hypertension is a major risk factor for nephrosclerosis and end-stage renal diseases (Appel et al, 2010)
There was no significant difference in systolic blood pressure (SBP) among all groups of mice at baseline
The present study showed that the depletion of macrophages by liposome-encapsulated clodronate (LEC) induced a rapid reversal of high blood pressure in Ang II-infused mice (Ang II) mice
Summary
Hypertension is a major risk factor for nephrosclerosis and end-stage renal diseases (Appel et al, 2010). Recent studies suggest that immune cells, for monocyte/macrophage lineage, play a critical role in the pathogenesis of hypertensive renal injury (Tian and Chen, 2015; Wenzel et al, 2016). Infiltrated and activated monocytes/macrophages release chemokines and cytokines which may cause renal inflammation, endothelial dysfunction, glomerular and tubule sclerosis, and fibrosis (Wang and Harris, 2011). Immunosuppressive therapies reduce blood pressure and the number of infiltrated macrophages in the kidney and improve renal function in a variety of experimental hypertensive animals (Tian et al, 2007; McMaster et al, 2015). There are still no studies that have manipulated the level of macrophages to examine their direct role in hypertensive renal damage
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