Abstract-Angiotensin II (Ang II)-induced hypertension is associated with an inflammatory response that may contribute to the development of target organ damage. We tested the hypothesis that, in Ang II-induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in the development of renal fibrosis, damage, and dysfunction by causing oxidative stress, macrophage infiltration, and cell proliferation. To test this hypothesis, we used CCR2 knockout mice (CCR2 Ϫ/Ϫ ). The natural ligand of CCR2 is monocyte chemoattractant protein-1, a chemokine important for macrophage recruitment and activation. CCR2Ϫ/Ϫ and age-matched wild-type (CCR2 ϩ/ϩ ) C57BL/6J mice were infused continuously with either Ang II (5.2 ng/10 g per minute) or vehicle via osmotic minipumps for 2 or 4 weeks. Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in both strains of mice. However, in CCR2Ϫ/Ϫ mice with Ang II-induced hypertension, oxidative stress, macrophage infiltration, albuminuria, and renal damage were significantly decreased, and glomerular filtration rate was significantly higher than in CCR2 ϩ/ϩ mice. We concluded that, in Ang II-induced hypertension, CCR2 activation plays an important role in the development of hypertensive nephropathy via increased oxidative stress and inflammation. Key Words: inflammation Ⅲ chemokine receptors Ⅲ macrophage Ⅲ reactive oxygen species Ⅲ kidney diseases Ⅲ albuminuria Ⅲ fibrosis H ypertension is a major risk factor for renal nephrosclerosis; however, the mechanisms by which high blood pressure causes renal damage are not completely understood. Angiotensin II (Ang II), in addition to causing vasoconstriction, aldosterone release, and Na reabsorption by the nephron, also causes oxidative stress, inflammation, cell proliferation, and, as a consequence, interstitial matrix accumulation and target organ damage. In the kidney, Ang II causes renal inflammation by stimulating superoxide formation and increasing chemokine release. [1][2][3] Chemokines are a family of low-molecular-weight cytokines that induce activation and migration of inflammatory cells and modulate functions of these cells. Monocyte chemoattractant protein (MCP-1) is one of the most prominent chemokines that regulates monocyte-macrophage infiltration. MCP-1 acts via its receptor, the CC chemokine receptor 2 (CCR2). 4,5 In mice lacking CCR2 (CCR2 Ϫ/Ϫ ), Ang II-induced vascular inflammation and remodeling are significantly reduced. 6 In a unilateral ureteral obstruction model of renal fibrosis and inflammation, CCR2 blockade ameliorates fibrosis and macrophage infiltration. 7,8 Although these studies suggest that MCP-1/CCR2 activation, via macrophage infiltration, plays a crucial role in the development of vascular and renal damage, it is unknown whether it contributes to renal damage and dysfunction in hypertension. Here we test the hypothesis that, in Ang II-induced hypertension, CCR2 activation plays an important role in the development of renal fibrosis, damage, a...