Chemokine Receptor CCR1 but Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Abstract

As chemokine receptor CCR1 and CCR5 expression on circulating leukocytes is thought to contribute to leukocyte recruitment during renal fibrosis, the authors examined the effects of unilateral ureteral obstruction (UUO) in mice deficient for CCR1 or CCR5. Analysis of UUO kidneys from CCR1-deficient mice revealed a reduction of interstitial macrophages and lymphocytes (35% and 55%, respectively) compared with wild-type controls. CCR1-deficient mice had reduced CCR5 mRNA levels in UUO kidneys, which correlated with a reduction of CCR5+ T cell infiltrate as determined by flow cytometry. Interstitial fibroblasts, renal TGF-β1 mRNA expression, interstitial volume, and collagen 1 deposits were all significantly reduced in CCR1-deficient mice. In contrast, renal leukocytes and fibrosis were unaffected in CCR5-deficient mice with UUO. However, if treated with the CCR1 antagonist BX471, CCR5-deficient mice showed a similar reduction of renal leukocytes and fibrosis as CCR1-deficient mice. To determine the underlying mechanism labeled macrophages and T cells isolated from either wild-type, CCR1-deficient, or CCR5-deficient mice were injected into wild-type mice with UUO. Three hours later, renal cell recruitment was reduced for CCR1-deficient cells or cells pretreated with BX471 compared with CCR5-deficient or wild-type cells. Thus, CCR1 but not CCR5 is required for leukocyte recruitment and fibrosis after UUO in mice. Therefore, CCR1 is a promising target for therapeutic intervention in leukocyte-mediated fibrotic tissue injury, e.g. progressive renal fibrosis.