Absence of the lysosomal protein Limp-2 attenuates renal injury in crescentic glomerulonephritis

Darren Hiu Kwong Lee, Poh Yi Gan, Marina Katerelos, Scott Andrew Fraser, Kurt Gleich, Stephen Roger Holdsworth, David Anthony Power

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)400 - 408
Number of pages9
JournalImmunology and Cell Biology
Volume92
Issue number5
DOIs
Publication statusPublished - 2014

Cite this

Lee, Darren Hiu Kwong ; Gan, Poh Yi ; Katerelos, Marina ; Fraser, Scott Andrew ; Gleich, Kurt ; Holdsworth, Stephen Roger ; Power, David Anthony. / Absence of the lysosomal protein Limp-2 attenuates renal injury in crescentic glomerulonephritis. In: Immunology and Cell Biology. 2014 ; Vol. 92, No. 5. pp. 400 - 408.
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abstract = "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.",
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Absence of the lysosomal protein Limp-2 attenuates renal injury in crescentic glomerulonephritis. / Lee, Darren Hiu Kwong; Gan, Poh Yi; Katerelos, Marina; Fraser, Scott Andrew; Gleich, Kurt; Holdsworth, Stephen Roger; Power, David Anthony.

In: Immunology and Cell Biology, Vol. 92, No. 5, 2014, p. 400 - 408.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Lee, Darren Hiu Kwong

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AU - Katerelos, Marina

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AU - Gleich, Kurt

AU - Holdsworth, Stephen Roger

AU - Power, David Anthony

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AB - 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.

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