High Glucose-Induced Expression of Proinflammatory Cytokine and Chemokine Genes in Monocytic Cells

Shanmugam, Narkunaraja; Reddy, Marpadga A.; Guha, Mausumee; Natarajan, Rama

doi:10.2337/diabetes.52.5.1256

Cited by 482 publications

(395 citation statements)

References 49 publications

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“…We could not exclude the possibility that the diabetesinduced circadian augmentation of PAI-1 expression was caused by a CLOCK-regulated indirect mechanism, because the transcription of PAI-1 mRNA is regulated by multiple signals such as those from insulin precursors (proinsulin and split proinsulin) [34][35][36], glucose [37], lipids [38], reactive oxygen species [39], glucocorticoids [40], and inflammatory mediators such as transforming growth factor b (TGFb), tumor necrosis factor a (TNFa), and interleukin-1a (IL-1a) [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

et al. 2005

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Diabetes is associated with an excess risk of cardiac events, and one of the risk factors for infarction is the elevated-levels of plasminogen activator inhibitor-1 (PAI-1). To evaluate how the molecular clock mechanism is involved in the diabetes-induced circadian augmentation of PAI-1 gene expression, we examined the expression profiles of PAI-1 mRNA in the hearts of Clock mutant mice with streptozotocin-induced diabetes. Circadian expression of PAI-1 mRNA was blunted to low levels under both normal and diabetic conditions in Clock mutant mice, although the expression rhythm was augmented in diabetic wild-type (WT) mice. Furthermore, plasma PAI-1 levels became significantly higher in WT mice than in Clock mutant mice after STZ administration. Our results suggested that the circadian clock component, CLOCK, is involved in the diabetes-induced circadian augmentation of PAI-1 expression in the mouse heart.

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Section: Discussionmentioning

confidence: 99%

Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

et al. 2005

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“…High glucose directly up-regulates MCP-1 expression in vascular endothelial cells and monocytes [19,20]. MCP-1 mRNA is dramatically overexpressed (increased by a factor of seven) in white adipose tissue of genetically obese (ob/ob) mice compared with lean control mice [10].…”

Section: Introductionmentioning

confidence: 99%

Association between the A?2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus

et al. 2004

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Aims/hypothesis. The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance. Methods. We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort (n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively. Results. Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR (p=0.011), insulin resistance (p=0.0097) and diabetes (p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 (p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, p=0.0060) and diabetes (OR=0.80, p=0.018). Conclusions/interpretation. In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemia.

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“…10,19,20 Elements of the diabetic milieu, such as hyperglycemia and advanced glycation endproducts are thought to play an important role in creating a proinflammatory environment in both peripheral circulation and renal tissues. 10,14,21,22 Moreover, the initial renal glomerular dysfunction is thought to result in macrophage infiltration due to increased expression of inflammatory adhesion and chemoattractant proteins. 10 Infiltration of macrophages, the major inflammatory cells that mediate renal inflammation during DN and local chemokine production, lead to additional immune cell migration into the kidneys, as well as interaction with resident renal cells, which further exacerbates renal inflammation, injury, and fibrosis.…”

mentioning

confidence: 99%

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Bhatt

Lanting

Jia

et al. 2015

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Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a 2/2 mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a 2/2 than in the kidneys of wild-type mice. Notably, miR146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1b and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a 2/2 mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a 2/2 mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN. 27: 227727: -228827: , 201627: . doi: 10.1681 Diabetic nephropathy (DN) is the leading cause of CKD and ESRD. 1-6 Development and progression of DN involve a complex interplay among metabolic, hemodynamic, growth, and inflammatory factors. 1,3,[7][8][9][10][11][12][13] The progressive decline in renal function during DN is a result of a multitude of pathologic changes in the kidneys, including glomerular and tubular hypertrophy, macrophage infiltration, extracellular matrix (ECM) accumulation in multiple renal cells, mesangial expansion, endothelial dysfunction, and podocyte injury. 1,3,[7][8][9][10][11][12][14][15][16] These pathologic changes clinically manifest as proteinuria and a steady deterioration in GFR. 3,4,16 Identification of molecular pathways that contribute to the pathophysiology of DN is imperative for the development of new therapeutic strategies. J Am Soc NephrolConversely, identification of factors that exert adaptive and protective roles in the early stages of DN can be exploited to prevent progression to ESRD.

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High Glucose-Induced Expression of Proinflammatory Cytokine and Chemokine Genes in Monocytic Cells

Cited by 482 publications

References 49 publications

Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

Involvement of circadian clock gene Clock in diabetes‐induced circadian augmentation of plasminogen activator inhibitor‐1 (PAI‐1) expression in the mouse heart

Association between the A?2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

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