Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes

Balasubramanyam, Muthuswamy; Sivasubramanian, Aravind; Gokulakrishnan, Kuppan; Prabu, Paramasivam; Sathishkumar, C; Ranjani, Harish; Mohan, Viswanathan

doi:10.1007/s11010-011-0727-3

Cited by 209 publications

(173 citation statements)

References 43 publications

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“…TNF-α plays an important role in the development and progression of diabetic nephropathy supported by the observation of increases in renal TNF-α levels in diabetic animal models and patients (37,38), indicating that increased TNF-α levels result in renal damage. Clinical studies have reported significant increases in the renal production of IL-1β and IL-6 in patients with type 2 diabetic nephropathy compared with that in diabetic patients without nephropathy, suggesting a role of IL-1β and IL-6 in the pathogenesis of diabetic nephropathy (39,40). Similar to the aforementioned opposing effects of SIRT4 in glucose-induced podocytes, SIRT4 overexpression also attenuated the production of TNF-α, IL-1β and IL-6.…”

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confidence: 82%

SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

Shi

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Diabetic nephropathy is a diabetic complication associated with capillary damage and increased mortality. Sirtuin 4 (SIRT4) plays an important role in mitochondrial function and the pathogenesis of metabolic diseases, including aging kidneys. The aim of the present study was to investigate the association between SIRT4 and diabetic nephropathy in a glucose-induced mouse podocyte model. A CCK-8 assay showed that glucose simulation significantly inhibited podocyte proliferation in a time-and concentration-dependent manner. Reverse transcription-quantitative polymerase chain reaction and western blot analysis showed that the mRNA and protein levels of SIRT4 were notably decreased in a concentration-dependent manner in glucose-simulated podocytes. However, SIRT4 overexpression increased proliferation and suppressed apoptosis, which was accompanied by increases in mitochondrial membrane potential and reduced production of reactive oxygen species (ROS). Notably, SIRT4 overexpression downregulated the expression of apoptosis-related proteins NOX1, Bax and phosphorylated p38 and upregulated the expression of Bcl-2 in glucose-simulated podocytes. In addition, SIRT4 overexpression significantly attenuated the inflammatory response, indicated by reductions in the levels of TNF-α, IL-1β and IL-6. These results demonstrate for the first time that the overexpression of SIRT4 prevents glucose-induced podocyte apoptosis and ROS production and suggest that podocyte apoptosis represents an early pathological mechanism leading to diabetic nephropathy.

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confidence: 82%

SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

Shi

Wang

et al. 2016

Experimental and Therapeutic Medicine

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“…Expression of immune-modulatory miRNAs, especially miR-146a, has been determined in different diabetic complications, [48][49][50][51][52] including DN. 49,[53][54][55] While some studies have shown lower miR-146a expression during DN, 49 others have shown higher expression.…”

Section: Discussionmentioning

confidence: 99%

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

Bhatt

Lanting

Jia

et al. 2015

JASN

159

130

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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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“…Table 4 Correlation analysis between laboratory parameters and miRNAs in non-alcoholic fatty liver disease patients In one study, the miR-146a expression levels were significantly decreased in peripheral blood mononuclear cells from patients with Type 2 diabetes compared to control subjects. They also reported that reduced miR-146a levels are associated with insulin resistance and poor glycemic control [18] . Although miR-146a and miR-146b are encoded on different chromosomes, their mRNA targets are predicted to overlap significantly [19] .…”

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confidence: 99%

Circulating microRNAs in patients with non-alcoholic fatty liver disease

Celıkbılek¹,

Başkol²,

Taheri³

et al. 2014

WJH

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AIM:To identify novel non-invasive biomarkers for non-alcoholic fatty liver disease (NAFLD). METHODS:Twenty patients with histologically proven NAFLD and 20 controls were included. All NAFLD cases were scored using the NAFLD activity score. The relative expressions of miR-197, miR-146b, miR-10b, miR181d, miR-34a, miR-122, miR-99a and miR-29a were analyzed using real-time polymerase chain reaction. RESULTS:Serum levels of miR-181d, miR-99a, miR-197 and miR-146b were significantly lower in biopsy-proven NAFLD patients than in the healthy controls. Serum levels of miR-197 and miR-10b were inversely correlated with degree of inflammation and miR-181d and miR99a were inversely correlated with serum gamma glutamyl transferase levels in non-alcoholic steatohepatitis patients. CONCLUSION:NAFLD is associated with altered serum miRNA expression pattern. This study provides clues for defining the non-invasive diagnosis of NAFLD.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; MicroRNA; Noninvasive; Serum markers Core tip: Due to the limitations of liver biopsy, the use of non-invasive markers has emerged in recent years. MicroRNAs (miRNAs) are a class of naturally occurring small noncoding RNAs that regulate gene expression. Altered miRNA expression has been reported in animal and human liver samples in non-alcoholic fatty liver disease (NAFLD). There is, however, only limited information on their detection in blood and their correlation with histological disease severity in patients with NAFLD. For this reason, we measured the serum levels of some miRNAs in non-alcoholic steatohepatitis (NASH) patients. Of these microRNAs, miR-181d, miR99a, miR-197 and miR-146b were expressed at lower levels in NASH patients than in controls. Serum levels of miR-197 and miR-10b were inversely correlated with degree of inflammation and miR-181d and miR-99a were inversely correlated with serum gamma glutamyl transferase levels in NASH patients. Circulating microRNAs in patients with non-alcoholic fatty liver disease 613 Celikbilek M, Baskol M, Taheri S, Deniz K, Dogan S, Zararsız G, Gursoy S, Guven K, Ozbakır O, Dundar M, Yucesoy M. Circulating microRNAs in patients with non-alcoholic fatty liver disease. ORIGINAL ARTICLE

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Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes

Cited by 209 publications

References 43 publications

SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

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

Circulating microRNAs in patients with non-alcoholic fatty liver disease

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