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

Author(s)

Cassini, Marcelo F. ^{[1, 2]} ; Kakade, Vijayakumar R. ^[1] ; Kurtz, Elizabeth ^{[1, 3]} ; Sulkowski, Parker ^{[4, 5]} ; Glazer, Peter ^{[4, 5]} ; Torres, Richard ^[6] ; Somlo, Stefan ^[1] ; Cantley, Lloyd G. ^[1]

Affiliation

^[1] Yale Univ, Sch Med, Dept Med, Sect Nephrol, Box 208029, 333 Cedar St, New Haven, CT 06510 - USA

^[2] Westchester Med Ctr, Dept Pathol, Valhalla, NY - USA

^[3] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 - USA

^[4] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 - USA

^[5] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 - USA

^[6] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 - USA

• Document type: Journal article
• Source: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY; v. 29, n. 10, p. 2471-2481, OCT 2018.
• Web of Science Citations: 7

Abstract

Background: In patients with autosomal dominant polycystic kidney disease (ADPKD), most of whom have a mutation in PKD1 or PKD2, 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. Methods: To define the role of Mcp1 and macrophages in promoting cyst growth, we used mice with inducible knockout of Pkd1 alone (single knockout) or knockout of both Pkd1 and Mcp1 (double knockout) in the murine renal tubule. Levels of Mcp1 RNA expression were measured in single-knockout mice and controls. Results: In single-knockout mice, upregulation of Mcp1 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 Mcp1 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 Mcp1 knockout. Conclusions: Mcp1 is upregulated after knockout of Pkd1 and promotes macrophage accumulation and cyst growth via both proliferation-independent and proliferation-dependent mechanisms in this orthologous mouse model of ADPKD. (AU)

• FAPESP's process: 13/16376-0 - Polycystic kidney disease: the chemical signals of polycystin 1 (PC1) attract monocytes for renal cysts, stimulating its growth and contributing to the deterioration of renal function
• Grantee: Marcelo Ferreira Cassini
• Support type: Scholarships abroad - Research