Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy

• Published in: American journal of physiology. Renal physiology Vol. 297; no. 5; pp. F1229 - F1237
• Main Authors: Min, Danqing, Lyons, J Guy, Bonner, James, Twigg, Stephen M, Yue, Dennis K, McLennan, Susan V
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.11.2009
• Subjects: Animals; CD11b Antigen - biosynthesis; Cell Adhesion; Cell adhesion & migration; Cell culture; Cell Line; Cells; Cells, Cultured; Chemotaxis, Leukocyte - physiology; Cytokines; Cytokines - metabolism; Diabetes; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - pathology; Flow Cytometry; Gene expression; Humans; Inflammation - pathology; Kidneys; Leukocyte Count; Macrophages - physiology; Male; Matrix Metalloproteinase 9 - metabolism; Mesangial Cells - physiology; Monocytes - physiology; Nephrology; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - physiology; Tissue Inhibitor of Metalloproteinases - metabolism
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00074.2009

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.