Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in <i>Pkd1</i>-Deficient Mice.

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is the leading inherited renal disease worldwide. The proproliferative function of macrophages is associated with late-stage cyst enlargement in mice with PKD; however, the way in which macrophages act on cyst-lining epithelial cells (CLECs) has not been well elucidated. We generated a rapid-onset PKD mouse model by inactivating <i>Pkd1</i> on postnatal day 10 (P10) and compared cell proliferation and differential gene expression in kidney tissues of the PKD mice and wild-type (WT) littermates. The cystic phenotype was dominant from P18. A distinct peak in cell proliferation in polycystic kidneys during P22-P30 was closely related to late-stage cyst growth. Comparisons of gene expression profiles in kidney tissues at P22 and P30 in PKD and WT mice revealed that arginine metabolism was significantly activated; 204 differentially expressed genes (DEGs), including <i>Arg1</i>, an arginine metabolism-associated gene, were identified in late-stage polycystic kidneys. The <i>Arg1</i>-encoded protein, arginase-1 (ARG1), was predominantly expressed in macrophages in a time-dependent manner. Multiple-stage macrophage depletion verified that macrophages expressing high ARG1 levels accounted for late-stage cyst enlargement, and inhibiting ARG1 activity significantly retarded cyst growth and effectively lowered the proliferative indices in polycystic kidneys. <i>In vitro</i> experiments revealed that macrophages stimulated CLEC proliferation, and that L-lactic acid, primarily generated by CLECs, significantly upregulated ARG1 expression and increased polyamine synthesis in macrophages. Interactions between macrophages and CLECs promote cyst growth. ARG1 is a key molecule involved in this process and is a potential therapeutic target to help delay ADPKD progression.