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Updated: Apr 16, 2026
Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
S100A8/A9 (calprotectin) is critical for development of glomerulonephritis and promotes inflammatory leukocyte-renal
Ruth J Pepper1, Hsu-Han Wang1, Gayathri K Rajakaruna1
1UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
Insights
S100A8/A9, also known as myeloid-related protein (MRP) 8/14 or calprotectin, exacerbates glomerulonephritis by amplifying inflammation. Blocking S100A8/A9 may offer a new therapeutic strategy for kidney disease.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Glomerulonephritis is a significant cause of end-stage renal disease.
- Leukocyte interactions with renal cells are crucial in glomerulonephritis pathogenesis.
- The precise mechanisms driving glomerulonephritis progression remain incompletely understood.
Purpose of the Study:
- To investigate the role of S100A8/A9 (myeloid-related protein [MRP] 8/14, calprotectin) in promoting glomerulonephritis.
- To explore S100A8/A9 as a potential therapeutic target for glomerulonephritis.
Main Methods:
- Utilized a murine model of nephrotoxic nephritis.
- Compared wild-type (WT) mice with S100a9(-/-) knockout mice deficient in MRP14.
- Employed bone marrow transplantation experiments to assess cell-specific roles.
- Conducted in vitro studies using macrophages, mesangial cells, and endothelial cells.
Main Results:
- Elevated serum S100A8/A9 levels were observed in WT mice with glomerulonephritis.
- S100a9(-/-) mice were significantly protected from glomerulonephritis development.
- MRP14 deficiency in both hemopoietic and intrinsic cells conferred protection.
- S100A8/A9 stimulation induced pro-inflammatory cytokine secretion (IL-6, CXCL1, TNF-α) in WT cells, with blunted responses in Mrp14(-/-) cells.
- S100A8/A9 amplified pro-inflammatory cytokine release upon interaction between macrophages and endothelial cells.
Conclusions:
- S100A8/A9 plays a critical role in glomerulonephritis by mediating pro-inflammatory effects on immune and renal cells.
- S100A8/A9 amplifies inflammation through autocrine and paracrine mechanisms.
- Targeting S100A8/A9 represents a potential novel therapeutic strategy for managing glomerulonephritis.
Abstract:
Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerulonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (S100a9(-/-)), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow-derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor α; however, Mrp14(-/-) cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow-derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14(-/-) bone marrow-derived macrophages. Data shows that S100A8/A9 plays a critical role during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow-derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis.
