Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchymal cells during kidney disease. To investigate whether MCP-1 promotes tubular and/or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and glomeruli were severely damaged in the MCP-1-intact strain (day 7). MCP-1 transcripts increased fivefold in MCP-1-intact mice. MCP-1 was predominantly localized within cortical tubules (90%), and most cortical tubules were damaged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, there was a marked reduction (>40%) in tubular injury in MCP-1-deficient mice (histopathology, apoptosis). MCP-1-deficient mice were not protected from glomerular injury (histopathology, proteinuria, macrophage influx). Macrophage accumulation increased adjacent to tubules in MCP-1-intact mice compared with MCP-1-deficient mice (70%, P < 0.005), indicating that macrophages recruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysaccharide-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, promotes TEC and not glomerular damage, and increases activated macrophages adjacent to TEC that damage TEC during NSN. Therefore, we suggest that blockage of TEC MCP-1 expression is a therapeutic strategy for some forms of kidney disease.

MCP-1 Induces Inflammatory Activation of Human Tubular Epithelial Cells

“…Furthermore, MCP-1 plays a role in hypertensive renal damage in the two-kidney one-clip rat model (31), which is possibly mediated by angiotensin II (32). Interestingly, MCP-1-deficient mice compared with wild-type mice exhibit no differences in glomerular lesions in nephrotic serum-induced nephritis, but exhibit less tubulointerstitial lesions (33). These reports support an important role of locally produced MCP-1 on the initiation and progression of renal damage, particularly tubulointerstitial damage.…”

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…Use of this experimental tool has been instrumental in demonstrating the potential pathogenic role of several mediators, including a variety of adhesion molecules, chemokines, and cytokines (23)(24)(25)(26)(27)(28)(29). Proteinuria is typically the first indicator that surfaces in both experimental and spontaneous immune nephritis (1)(2)(3)(4)(5).…”

Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali injury model in mice

“…MCP-1 is a chemokine which induces chemotaxis of monocytes/macrophages into an injured tissue, and is upregulated by, in part, TGF-b signaling. 53,54 Real-time RT-PCR showed that ectopic BMP-7 expression suppressed upregulation of mRNA expression of TGF-b1 and MCP-1 in healing, burned, corneas at both Days 10 and 20, whereas expression of VEGF mRNA was not reduced at Day 10 ( Figure 7a-c). Immunohistochemical staining in paraffin sections also showed that TGF-b1 and 2 were both expressed in the epithelium of the uninjured cornea (Figure 7d).…”