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

Abstract

Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am J Physiol Renal Physiol 297: F1229 -F1237, 2009. First published September 9, 2009 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-␣, 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-␣, IL-6, and macrophage number and colocalization of MMP-9 with macrophage were increased (P Ͻ 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 Ͻ 0.05) and conditioned media degradative activity (5 mM: 30.0% and 25 mM: 33.5%: P Ͻ 0.05). These effects were reproduced by addition of mesangial cell conditioned medium to THP1 cells. High glucose (25 mM) increased TNF-␣, IL-6, and monocyte chemoattractant protein-1 in mesangial cell conditioned medium. These cytokines all increased adhesion and differentiation of THP1 cells (P Ͻ 0.05), but only TNF-␣ and IL-6 increased MMP-9 expression (50-and 60-fold, respectively; P Ͻ 0.05). Our results show that mesangial cellsecreted 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. matrix metalloproteinases; matrix degradation; cell adhesion and infiltration; inflammation response

Drugs for Diabetic Nephropathy- Full Review

“…Il-6-secreted by renal cell in response to diabetic milieu [105] Significant association between severity of diabetic glomerulopathy and IL-6 level [107] IL-6 level are increased in diabetic patient as compared to normal [106] High level of IL-6 are reported in diabetic patient and correlates with urinary albumin excretion and High sensitive CRP level [108] same result were found in other study in type 1 diabetes patient IL-6 level were high and correlated with urinary albumin excretion [109] IL-6 SIGNALLING -IL-6 activate its receptor and brings about activation of JAK/STAT pathway and STAT 3 protein is translocate in nucleus and enhance transcription factors [110] EFFECTS OF IL-6 [111] 1) Promote Growth And Proliferation Of Mesangial Cells 2) Extracellular Matrix Accumulation 3) Glomerular Basement Membrane (GBM) thickening…”

Microinflammation as a Candidate for Diabetic Nephropathy

“…Besides, hyperglycemia induces mesangial fibrosis that requires activation of interleukin (IL)-8. As a contributor in renal inflammation, high glucose promotes mesangial production of macrophage chemoattractant protein-1 (MCP-1 also known as CCL2, CC chemokine ligand 2), IL-6, and tumor necrosis factor (TNF)-α, which, together with adhesion molecules, favor leukocyte recruitment and adhesion to endothelial cells [14,15].…”

“…The subsequent events for this intracellular signaling in glomerular endothelial cells include endothelial dysfunction, inflammation and microvascular thrombosis [14,15].…”

“…Concurrently, hyperglycemia hastens renal inflammatory monocyte/macrophage infiltration and adhesion provoked by the vascular pathological environment and by increasing proinflammatory cytokine secretion from renal cells [14,15].…”

“…Increased renal expression of MCP-1 is considered to be important in the initiation of this process. In addition to MCP-1, IL-6, TNF-α and a variety of other chemokines produced by mesangial cells promote leukocyte recruitment and adhesion to endothelial cells [15]. This adhesion is mediated through mesangial activation of ICAM-1, VCAM-1, E-selectin, P-selectin and integrin-1, with the resulting attachment of inflammatory cells to vascular endothelial cells and their infiltration into both the glomeruli and the interstitium [38].…”