Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease.

Abstract

In patients with autosomal dominant polycystic kidney disease (ADPKD), most of whom have a mutation in <i>PKD1</i> or <i>PKD2</i>, abnormally large numbers of macrophages accumulate around kidney cysts and promote their growth. Research by us and others has suggested that monocyte chemoattractant protein-1 (Mcp1) may be a signal for macrophage-mediated cyst growth. To define the role of Mcp1 and macrophages in promoting cyst growth, we used mice with inducible knockout of <i>Pkd1</i> alone (single knockout) or knockout of both <i>Pkd1</i> and <i>Mcp1</i> (double knockout) in the murine renal tubule. Levels of <i>Mcp1</i> RNA expression were measured in single-knockout mice and controls. In single-knockout mice, upregulation of <i>Mcp1</i> precedes macrophage infiltration. Macrophages accumulating around nascent cysts (0-2 weeks after induction) are initially proinflammatory and induce tubular cell injury with morphologic flattening, oxidative DNA damage, and proliferation-independent cystic dilation. At 2-6 weeks after induction, macrophages switch to an alternative activation phenotype and promote further cyst growth because of an additional three-fold increase in tubular cell proliferative rates. In double-knockout mice, there is a marked reduction in <i>Mcp1</i> expression and macrophage numbers, resulting in less initial tubular cell injury, slower cyst growth, and improved renal function. Treatment of single-knockout mice with an inhibitor to the Mcp1 receptor Ccr2 partially reproduced the morphologic and functional improvement seen with <i>Mcp1</i> knockout. Mcp1 is upregulated after knockout of <i>Pkd1</i> and promotes macrophage accumulation and cyst growth <i>via</i> both proliferation-independent and proliferation-dependent mechanisms in this orthologous mouse model of ADPKD.