The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility and albumin permeability

Abstract

The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert noninflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-beta (TGF-beta) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-beta type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-beta-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-beta were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF-beta signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria.

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

“…Secretory factors from macrophages may cause histological and functional changes in glomeruli. For example, TGF β1 (TGFB1) and MCP1, induced in surrounding cells by or secreted directly from activated macrophages, have been shown to upregulate CTGF production [43] and increase albumin permeability in cultured podocytes [44][45][46]; we have recently reported that overproduction of CTGF specifically in podocytes is sufficient to worsen diabetic nephropathy [19].…”

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).…”

Role of the Mammalian Target of Rapamycin (mTOR) Signalling Pathway in Podocytes in Glomerular Disease

“…The main function of the slit diaphragm is to form a size-selective barrier for proteins and since many of the slit diaphragm proteins are phosphorylated, this contributes to the charge-selective element (Tryggvason K, 2001). Podocyte-specific multiprotein complexes, similar to adherens junctions, extend between the filtration slits, closely interact with the actin cytoskeleton, influencing signaling pathways and motility of the podocyte (Lee et al, 2009) (Burt et al, 2007) and thereby establishing the final barrier to urinary protein loss (Somlo and Mundel, 2000). The proteins which make up the slit diaphragm system are nephrin, Neph1, Neph2, podocin, fatty acid transporter tumor suppressor homolog-1 (FAT1) and FAT2, and the calcium channel transient receptor potential cation 6 (TRPC6) and cadherins (Harita Y, 2008) (Yaoita et al, 2005) (Liu G, 2003) (Dryer SE, 2010) .…”