The role of inflammation as a pathogenic factor in the development of renal disease in diabetes

Mora, Carmen; Navarro, Juan F.

doi:10.1007/s11892-005-0044-x

Cited by 38 publications

(36 citation statements)

References 27 publications

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“…[5][6][7] For example, macrophages produce proinflammatory mediators, eg, Ccl2, which add to the mediators produced by renal cells, ie, in a positive amplification loop. 20,48 This observation made in nondiabetic types of kidney disease is likely to apply also to diabetic nephropathy in humans, because interstitial macrophage infiltrates are common in diabetic nephropathy 19 and patients with diabetic nephropathy excrete high levels of Ccl2 into the urine, itself indicating intrarenal inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Data from recent experimental studies relate the progression of glomerulosclerosis in diabetic mice and humans to intrarenal inflammation. [5][6][7][8] For example, mycophenolate mofetil, methotrexate, or irradiation reduce urinary albumin excretion, and glomerulosclerosis in rats with streptozotocin-induced diabetes. 9,10 Yet, the molecular and cellular mechanisms of intrarenal inflammation in diabetic nephropathy remain poorly characterized.…”

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confidence: 99%

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Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36–3′PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice

Ninichuk¹,

Clauß²,

Kulkarni³

et al. 2008

The American Journal of Pathology

125

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Diabetic kidney disease is associated with monocyte chemoattractant CC chemokine ligand 2 (CCL2)-dependent glomerular and interstitial macrophage recruitment. In addition, nephropathy is delayed in Ccl2 mutant diabetic mice. However, whether the late onset of therapeutic Ccl2 blockade modulates the progression of advanced diabetic nephropathy remains unknown. We addressed this question by antagonizing Ccl2 with mNOX-E36 -3PEG, an anti-Ccl2 L-enantiomeric RNA aptamer (ie, a Spiegelmer), which binds murine Ccl2 and blocks the recruitment of ex vivo-labeled macrophages to the kidneys of db/db mice with type 2 diabetes. We injected mNOX-E36 -3PEG subcutaneously at a dose of 50 mg/kg three times per week into uninephrectomized (1K) db/db mice with advanced glomerulopathy from 4 to 6 months of age. mNOX-E36 -3PEG reduced the number of glomerular macrophages by 40% compared with nonfunctional (control) Spiegelmertreated 1K db/db mice. This result was associated with protection from diffuse glomerulosclerosis and significantly improved the glomerular filtration rate. mNOX-E36 -3PEG also reduced renal Ccl2 mRNA and protein expression compared with control Spiegelmer-treated 1K db/db mice of the same age. Together, the late onset of therapeutic Ccl2 blockade, eg, with specific Spiegelmers, offers protection from diffuse glomerulosclerosis in type 2 diabetic db/db mice and, thus, may represent a novel therapeutic strategy for advanced glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36–3′PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice

Ninichuk¹,

Clauß²,

Kulkarni³

et al. 2008

The American Journal of Pathology

125

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“…This would further augment mesangial cell secretion of cytokines and subsequent increased activation of monocytes. It is also well recognized that diabetes is an inflammatory condition, and the circulating concentrations of MCP-1, TNF-␣, and IL-6 are increased in diabetes (6,17) and are reported to correlate with the degree of proteinuria, glomerular macrophage number, and monocyte expression of CD11b (24). It is therefore possible that these cytokines, whether from mesangial cells or other sources, may exert systemically similar actions on monocytes.…”

Section: Discussionmentioning

confidence: 99%

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

Min

Lyons

Bonner

et al. 2009

American Journal of Physiology-Renal Physiology

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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

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“…2 Many types of study, such as in vitro experiments, pathological analyses and epidemiological studies, have shown that diabetic nephropathy is intrinsically an inflammatory disease. 3,4 Indeed, several papers have reported that monocyte chemoattractant protein-1 (MCP-1), a principal chemokine that mediates the recruitment of monocytes to inflammatory sites, plays a central role in the pathogenesis of diabetic nephropathy.…”

Section: Introductionmentioning

confidence: 99%

Telmisartan, an Angiotensin II Type 1 Receptor Blocker, Inhibits Advanced Glycation End-product (AGE)-induced Monocyte Chemoattractant Protein-1 Expression in Mesangial Cells through Downregulation of Receptor for AGEs via Peroxisome Proliferator-activated Receptor-γ Activation

et al. 2007

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Interaction between advanced glycation end-products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy pathogenesis. Pathophysiological crosstalk between the AGEs-RAGE system and angiotensin II (Ang II) is also involved in this disease. This study investigated the role of proliferatoractivated receptor-g (PPAR-g)-modulating activity on inhibition of monocyte chemoattractant protein (MCP-1) expression. Telmisartan, an Ang II type 1 receptor blocker, downregulated RAGE mRNA and inhibited superoxide generation and MCP-1 gene expression in mesangial cells; these processes were blocked by GW9662, a PPAR-g inhibitor.

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The role of inflammation as a pathogenic factor in the development of renal disease in diabetes

Cited by 38 publications

References 27 publications

Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36–3′PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice

Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36–3′PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice

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

Telmisartan, an Angiotensin II Type 1 Receptor Blocker, Inhibits Advanced Glycation End-product (AGE)-induced Monocyte Chemoattractant Protein-1 Expression in Mesangial Cells through Downregulation of Receptor for AGEs via Peroxisome Proliferator-activated Receptor-γ Activation

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