In humans, mutations of the intrinsic lysosomal
protein SCARB2 are associated with
myoclonic epilepsy, collapsing focal and
segmental glomerulosclerosis, and tubular
proteinuria. Mice with deficiency of Limp-2 (the murine homologue) develop tubular
proteinuria but not focal and
segmental glomerulosclerosis and they have a defect in macrophage function. To further elucidate the role of Limp-2 in immune function, we induced anti-glomerular basement membrane (GBM) model of crescentic
glomerulonephritis in wild-type (WT) and Limp-2(-/-) littermates by
intraperitoneal injections of nephrotoxic sheep serum. Renal injury and immune responses were assessed on day 14. Compared with WT, Limp-2(-/-) mice had significantly reduced crescent formation, interstitial
inflammation and a trend to reduced tubulointerstitial injury. On day 1 during the heterologous phase of the disease,
albuminuria was significantly increased in WT but not in Limp-2(-/-) mice. On day 14,
albuminuria and renal function were similar in the two groups. There was, however, a significant reduction in the influx of glomerular macrophages and CD4(+) T cells in Limp-2(-/-) mice.
Interleukin (IL)-4 and macrophage
chemoattractant protein-1 (MCP-1)
mRNA expression levels were significantly reduced. Despite the reduction in numbers of infiltrating cells, flow cytometry showed no difference in macrophage or T-cell numbers in the peripheral blood from untreated mice. The systemic humoral immune response, determined by glomerular mouse
immunoglobulin G (
IgG) deposition and mouse anti-sheep
IgG subclass production, was similar in both groups. These data suggest that absence of Limp-2 reduces
inflammation in experimental crescentic
glomerulonephritis with decreased macrophage and T-cell infiltration in the kidney. It suggests an important role for Limp-2 in mediating the inflammatory response.