THE ROLE OF MACROPHAGES IN THE PROGRESSION OF POLYCYSTIC KIDNEY DISEASE

Abstract

Polycystic kidney disease (PKD) is one of the most common potentially fatal genetic disorders. The most common form, autosomal dominant polycystic kidney disease (ADPKD), affects approximately 12.5 million individuals worldwide, and approximately 600,000 individuals in the US, over half of whom will develop end-stage renal disease (ESRD). Mutations in either the PKD1 or PKD2 genes are the primary cause of this disease, although, there is increasing evidence that non-genetic factors, including kidney injury and inflammatory responses, play a role in PKD progression. Infiltrating macrophages play an important part in kidney injury and repair as well as in chronic renal inflammatory diseases. Whether macrophages play a role in ADPKD cyst progression however, has remained largely unknown. Recent data from our lab and others have shown that macrophages accelerate disease progression by promoting ADPKD cell proliferation, a driving force behind cyst expansion and subsequent renal failure. In this study, we addressed the hypothesis that macrophages are recruited to the kidneys in response to chronic injury that is induced by progressively expanding cysts. Once in this environment, the injured renal cells stimulate the macrophages to undergo a phenotypic switch that, in turn, allows the macrophages to express pro-proliferative factors that are ultimately detrimental to the kidneys. Results presented in this study implicate MCP-1 as the predominant contributor to macrophage recruitment to the kidneys; while our MCP-1 knockout mouse model demonstrated a significant increase in survival of mice affected with PKD. In addition, we uncovered signaling through CXCR2 as a potential pathway in the programmed-macrophage-induced pro-proliferative response in ADPKD cyst cells. Experiments on the effect of WNT5A, the expression of which is upregulated in the presence of macrophages, on ADPKD cyst cell progression pointed towards its importance in the promotion of growth of ADPKD cyst cells. This study highlights the significance of macrophage-induced cell proliferation in the progression of PKD and uncovers several components that can be targeted for the design of drug therapies.