title: Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy.
abstract: Infiltration of macrophages to the kidney is a feature of early diabetic nephropathy. For this to happen monocytes must become activated, migrate from the circulation, and infiltrate the mesangium. This process involves degradation of extracellular matrix, a process mediated by matrix metalloproteinases (MMPs). In the present study we investigate the expression of proinflammatory cytokines TNF-alpha, IL-6, and MMP-9 in glomeruli of control and diabetic rodents and use an in vitro coculture system to examine whether factors secreted by mesangial cells in response to a diabetic milieu can induce monocyte MMP-9 expression and infiltration. After 8 wk of diabetes, the glomerular level of TNF-alpha, IL-6, and macrophage number and colocalization of MMP-9 with macrophage were increased (P < 0.01). Coculture of THP1 monocytes and glomerular mesangial cells in 5 or 25 mM glucose increased MMP-9 (5 mM: 65% and 25 mM: 112%; P < 0.05) and conditioned media degradative activity (5 mM: 30.0% and 25 mM: 33.5%: P < 0.05). These effects were reproduced by addition of mesangial cell conditioned medium to THP1 cells. High glucose (25 mM) increased TNF-alpha, IL-6, and monocyte chemoattractant protein-1 in mesangial cell conditioned medium. These cytokines all increased adhesion and differentiation of THP1 cells (P < 0.05), but only TNF-alpha and IL-6 increased MMP-9 expression (50- and 60-fold, respectively; P < 0.05). Our results show that mesangial cell-secreted factors increase monocyte adhesion, differentiation, MMP expression, and degradative capacity. High glucose could augment these effects by increasing mesangial cell proinflammatory cytokine secretion. This mesangial cell-monocyte interaction may be important in activating monocytes to migrate from the circulation to the kidney in the early stages of diabetic nephropathy.
authors.affiliation: Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. danqingm@med.usyd.edu.au
authors.forename: Danqing
authors.initials: D
authors.lastname: Min
authors.forename: J Guy
authors.initials: JG
authors.lastname: Lyons
authors.forename: James
authors.initials: J
authors.lastname: Bonner
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Twigg
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Yue
authors.forename: Susan V
authors.initials: SV
authors.lastname: McLennan
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007958:Leukocyte Count; D008264:Macrophages / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D050527:Mesangial Cells / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D019714:Tissue Inhibitor of Metalloproteinases; D020780:Matrix Metalloproteinase 9