The Monocyte Chemoattractant Protein-1/Cognate CC Chemokine Receptor 2 System Affects Cell Motility in Cultured Human Podocytes

Abstract

In crescentic glomerulonephritis (GN), monocyte chemoattractant protein-1 (MCP-1) is overexpressed within the glomeruli, and MCP-1 blockade has renoprotective effects. Adult podocytes are in a quiescent state, but acquisition of a migratory/proliferative phenotype has been described in crescentic GN and implicated in crescent formation. The cognate CC chemokine receptor 2 (CCR2), the MCP-1 receptor, is expressed by other cell types besides monocytes and has been implicated in both cell proliferation and migration. We investigated whether MCP-1 binding to CCR2 can induce a migratory/proliferative response in cultured podocytes. MCP-1 binding to CCR2 enhanced podocyte chemotaxis/haptotaxis in a concentration-dependent manner and had a modest effect on cell proliferation. Closure of a wounded podocyte monolayer was delayed by CCR2 blockade, and CCR2 was overexpressed at the wound edge, suggesting a role for CCR2 in driving podocyte migration. Immunohistochemical analysis of kidney biopsies from patients with crescentic GN demonstrated CCR2 expression in both podocytes and cellular crescents, confirming the clinical relevance of our in vitro findings. In conclusion, the MCP-1/CCR2 system is functionally active in podocytes and may be implicated in the migratory events triggered by podocyte injury in crescentic GN and other glomerular diseases. Podocytes are highly differentiated cells with a complex cellular morphology. The podocyte cell body bulges into the urinary space and gives rise to primary processes that extend toward the capillaries to which they affix by numerous foot processes. The foot process of neighboring podocytes interdigitate, leaving between them filtration slits bridged by an extracellular structure, known as the slit diaphragm, which represents the major restriction site to protein filtration. 1 In the adult kidney, podocytes are in a quiescent state; however, both proliferation and acquisition of a migratory phenotype have been reported in pathological conditions. In crescentic glomerulonephritis (GN), podocytes detach from the glomerular basement membrane (GBM), assume a migratory phenotype, and trigger crescent formation by establishing bridges between the tuft and the Bowman's capsule. 2 In addition, cells derived from migrated podocytes proliferate and participate in crescent formation. 3 Furthermore, in nephrotic conditions, podocyte effacement, which requires cytoskeleton remodeling, foot process movement over the GBM, and slit diaphragm reconstruction, may also be considered a migratory event aimed to compensate for podocyte loss by covering areas of bare GBM. 4 Monocyte chemoattractant protein-1 (MCP-1) is a potent mononuclear cell chemoattractant produced by a variety of mesenchymal cells, including glomerular cells. [5][6][7] Within the glomeruli, there is MCP-1 overexpression in both crescent GN 8 and nephrotic conditions. 9 -11 Furthermore, immunohistochemistry studies have shown that glomerular podocytes are the predominant glomerular cell type overexpressing MCP-1 in various prote...

Heat shock protein expression in diabetic nephropathy

“…Cultures of immortalized human podocytes and mesangial cells were established and characterized as previously described (2,12). Cells were cultured in DMEM (Invitrogen) containing L-glutamine, 6.8 mM glucose, 10 -20% heat-inactivated fetal calf serum (Euroclone Milan, Italy), 100 U/ml penicillin, and 100 g/ml streptomycin in a humidified 5% CO2 incubator at 37°C.…”

Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-κB and Smad2/3 Signaling

“…In addition to physical forces, an alternative mechanism for proteinuria could be attributable to humoral factors that are induced during the disease. For example, inflammatory cytokines or fibrogenic mediators had been shown to modulate podocyte motility and albumin permeability, mRNA expression of podocyte markers such as nephrin and ezrin as well as podocyte survival and adhesion (9)(10)(11)(12)(13)(14)(15). Presumably, through mesangial cellpodocyte communication (16)(17)(18), these effects might lead to breakdown of the glomerular permeability with resultant formation of proteinuria.…”

“…Inflammatory cytokines and fibrogenic mediators have been shown to modulate podocyte motility and albumin permeability in vitro (9)(10)(11)(12)(13). And mesangialderived cytokines such as tumor necrosis factor (TNF)-α or transforming growth factor (TGF)-β1 can inhibit the expression of nephrin and ezrin by podocytes and induce podocyte death and detachment (14,15).…”

Renal accumulation of macrophages in experimental polycystic kidney disease is reduced by bindarit

“…It has been recognized that in kidney disease MCP-1 acts deleteriously in ways that may accrue beyond its capability to attract macrophages and foster inflammation [20][21][22] . In PCK rats, the anti-MCP-1 therapy, besides having a remarkable anti-inflammatory effect, ameliorated renal function and significantly reduced proteinuria [19] .…”