Abstract
Background Response Gene to Complement (RGC)-32 is a cell cycle regulator induced by complement activation, growth factors and cytokines. RGC-32 mediates TGF-β dependent profibrotic pathways, while in immune cells promotes the differentiation of Th17 cells. In the nephrotoxic nephritis (NTN) mouse model of glomerulonephritis (GN), RGC-32 promotes organ damage through proinflammatory and profibrotic effects. To define the mechanisms underlying the role of RGC-32 in immune complex GN, we induced NTN in WT and RGC-32-/- mice.
Methods Proteinuria, blood urea nitrogen and kidney histopathology were determined to assess kidney damage. Single cell suspension of infiltrating kidneys and spleens cells were analyzed by flow cytometry and PCR for expression of IL-17A, CCR6, CCL20, CXCL1, CXCL2 and CXCL5.
Results Induction of NTN in RGC-32-/- mice resulted in decreased expression of IL-17A and CCR6 mRNA and decreased proportion of renal IL-17A+ CD4 T cells. The decrease in IL-17A+ CD4 cells was paralleled by decreased mRNA expression of CCL20 in both the renal tissue and infiltrating kidney cells of RGC-32-/- mice. In vitro, CD4+ T cells from spleens of RGC-32-/- mice cultured under Th17 conditions displayed decreased expression of CCL20 mRNA. These data suggest a role for RGC-32 in the positive feedback loop that enhances Th17 cell recruitment. The decrease in renal IL-17A+ cells was associated with decreased expression of IL-17 induced chemokines CXCL1, CXCL2 and CXCL5 and decreased local infiltration of neutrophils.
Conclusions These data suggest a role for RGC-32 in the positive feedback loop that enhances Th17 cell recruitment. The decrease in renal IL-17A+ cells was associated with decreased expression of IL-17 induced chemokines CXCL1, CXCL2 and CXCL5 and decreased local infiltration of neutrophils.
