Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice

Chow, Fiona Yf; Nikolic‐Paterson, David J.; Ma, Frank; Ozols, Elyce; Rollins, Barrett J.; Tesch, Gregory H

doi:10.1007/s00125-006-0497-8

Cited by 221 publications

(194 citation statements)

References 39 publications

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“…4,6 MCP-1 or ICAM-1 deficiency also prevent nephropathy in type II diabetic db/db mice. 5,7 We found another key molecule for the inflammation in diabetic nephropathy in the current study.…”

Section: Discussionsupporting

confidence: 58%

“…We do not exclude the possibility that these phenomena are secondary to the reduced glomerular injury and the lower level of proteinurea found in Mdk À/À mice. 10 Considering that a deficiency of MCP-1 or ICAM-1 causes a reduction of diabetic nephropathy, [4][5][6][7] it is noteworthy that only MCP-1 expression, that is, not that of ICAM-1, was affected in Mdk À/À mice. Therefore, the effect of MK deficiency may be attributable to the suppression of MCP-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…The percentage of atrophic tubules (tubular dilation, detachment of tubular epithelial cells (TECs) and condensation of tubular nuclei) was assessed by scoring 400 renal cortical tubules in randomly selected fields for each subject. [5][6][7] Eight subjects were examined for each experimental group. For the morphometric analysis, the extent of interstitial fibrosis was determined by assessing the Masson-trichrome-positive areas within the renal cortex excluding glomerulus.…”

Section: Morphological Assessmentmentioning

confidence: 99%

“…[3][4][5][6][7] However so far, only a few molecules have been identified as key players in this inflammation, that is, monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, nuclear factor-kB (NF-kB) and tumor necrosis factor-a. [3][4][5][6][7][8][9] We recently demonstrated that the growth factor midkine (MK) plays a critical role in the pathogenesis of diabetic nephropathy, using a mouse diabetes model induced by Streptozotocin (STZ). 10 STZ impairs b-cells in the pancreas, thereby inducing hyperglycemia, and thus has been used to induce type I diabetes mellitus in model systems.…”

mentioning

confidence: 99%

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Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Kosugi

Yuzawa

Sato

et al. 2007

Laboratory Investigation

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The concept that inflammation plays a crucial role in the pathogenesis of diabetic nephropathy has been recently emerging, although the principal pathology of diabetic nephropathy comprises glomerular sclerosis and associated changes in nephrons. Here, we identified the growth factor midkine (MK) as a novel key molecule involved in inflammation associated with Streptozotocin-induced diabetic nephropathy. The tubulointerstitial damage, as assessed as morphological changes, osteopontin expression, collagen I deposition and macrophage infiltration, were strikingly less in MK-deficient (Mdk À/À ) mice than in Mdk þ / þ mice. Monocyte chemoattractant protein (MCP)-1 expression, but not that of intercellular adhesion molecule-1, was also lower in Mdk À/À mice. High glucose upregulated MK expression in primarycultured tubular epithelial cells, and induced MCP-1 to a larger extent in Mdk þ / þ cells than in Mdk À/À cells. Correspondingly, the combination of exogenous MK and high glucose enhanced MCP-1 expression in Mdk À/À cells. Furthermore, high glucose and oxidant stress enhanced MK expression in macrophages. Consistent with the findings in the mouse model, MK expression was detected in the glomeruli, tubular epithelium and interstitium of kidneys from patients with diabetic nephropathy. Our data indicate that MK plays a critical role in the tubulointerstitial inflammation associated with diabetic nephropathy through activation of the MCP-1 pathway.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Morphological Assessmentmentioning

confidence: 99%

mentioning

confidence: 99%

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Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Kosugi

Yuzawa

Sato

et al. 2007

Laboratory Investigation

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“…The macrophage has been presumed to be a critical mediator of diabetic nephropathy [36][37][38], and blockade of the MCP-1/CC chemokine receptor 2 system in diabetic mice leads to reduced albuminuria, mesangial expansion and macrophage infiltration [39][40][41][42]. Secretory factors from macrophages may cause histological and functional changes in glomeruli.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellularmatrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

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Ethnic variation of IL‐4 intron 3 VNTR gene polymorphism; its association with type 2 diabetes mellitus and its complication (neuropathy) in Egyptian subjects

Ali

Elsaid

El-Baz

et al. 2018

American J of Med Genetics Pt B

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Type 2 diabetes mellitus (T2DM) has multigenetic and environmental interactive factors. Although diabetic neuropathies (DPN) are the most common, but at the same time, the least recognized and understood long‐term complication of diabetes. This study aimed to investigate the association of IL‐4 VNTR gene polymorphism with T2DM complicated with neuropathy in Egyptian subjects. This is a case control study including 102 T2DM Egyptian patients, plus 188 unrelated healthy individuals as controls. They were evaluated for variable number tandem repeat (VNTR); 70 base pair repeats located in the intron 3; of IL‐4 gene using the PCR technique. Homozygote frequency of the three‐repeat allele (A1/A1) genotype of IL‐4 VNTR was nearly equal among diabetic cases and controls (60.8% vs. 62.2%, respectively). Heterozygous frequency of (A1/A2) genotype was higher among controls compared to cases (33.5% vs. 19.6%, respectively) but not statistically significant. The (A2) allele had a significantly higher frequency in diabetic cases compared to controls (29.3% vs. 21.0%, respectively) while the (A1) allele had lower frequency but not significant one (70.7% vs. 79.0%, respectively). Comparing cases complicated with diabetic neuropathy vs. noncomplicated cases regarding their polymorphic IL‐4 (VNTR) genotypes revealed a nonsignificant lower frequency of (A1A1) genotype (57.1% vs. 65.1%, respectively, p = .57) with a higher combined (A2A2 + A1/A2) genotype frequency (42.9% vs. 34.9%, respectively). Only two haplotypes (A1) & (A2) of IL‐4 (VNTR) gene were recognized among Egyptian population; (A2) allele may influence in diabetes but not its complication (neuropathy) among Egyptian diabetic patients.

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Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice

Cited by 221 publications

References 39 publications

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

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

Ethnic variation of IL‐4 intron 3 VNTR gene polymorphism; its association with type 2 diabetes mellitus and its complication (neuropathy) in Egyptian subjects

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