Molecular mechanisms of diabetic kidney disease

Reidy, Kimberly; Kang, Hyun Mi; Hostetter, Thomas H.; Suszták, Katalin

doi:10.1172/jci72271

Cited by 722 publications

(604 citation statements)

References 105 publications

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“…Inflammation plays an important role throughout the pathogenesis of diabetic microvascular complications [28,30,31]. Kowluru et al showed that high glucose significantly increased the activated caspase-3 and NF-κB levels, which remained Bar, mean ± SD; **p < 0.01 vs the respective negative control groups.…”

Section: Discussionmentioning

confidence: 99%

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

Zhao

et al. 2015

Diabetologia

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Aims/hypothesis The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy. Methods The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs. Results High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression. Conclusions/interpretation These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucoseinduced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.

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Section: Discussionmentioning

confidence: 99%

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

Zhao

et al. 2015

Diabetologia

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“…Loss of this protective mechanism in miR-146a Diabetic nephropathy (DN) is the leading cause of CKD and ESRD. [1][2][3][4][5][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.…”

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confidence: 99%

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

Bhatt

Lanting

Jia

et al. 2015

JASN

158

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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“…Tubular dysfunction has been reported in the absence of microalbuminuria in patients with diabetes mellitus. Early tubular injury has been reported in patients with diabetes mellitus whose glomerular function is intact [7].…”

Section: Discussionmentioning

confidence: 99%

“…The hypoxic milieu in early stage diabetic nephropathy is aggravated by manifestations of chronic hyperglycemia-abnormalities of red blood cells, oxidative stress, sympathetic denervation of the kidney due to autonomic neuropathy, and diabetes-mellitus-induced tubular apoptosis; as such, tubulointerstitial hypoxia in diabetes mellitus might be an important early event [7][8][9]. Analysis of the Vitamin D3 levels in relation to albuminuria levels in patients with diabetic nephropathy shows negative correlation (R=-0.59, р<0.001) ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Beyond Proteinuria: Apoptosis and Vitamin D3 State in Children with Diabetic Nephropathy

Burlaka¹

2016

J Clin Exp Pathol

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Diabetic nephropathy (DN) is the leading cause of death in patients with diabetes mellitus type I (T1D). Formation of diabetic nephropathy depends on the quality of blood glucose control.The aim of the study was to investigate the level of metabolic-hypoxic disorders, condition of apoptosis controlling system and Vitamin D3 levels in children with diabetic nephropathy.The study involved 36 children with type I diabetes and diabetic nephropathy (aged 6 to 17 years). The affinity of haemoglobin to oxygen determined by spectrophotometric method. The levels of the marker of cellular hypoxia HIF-1alfa, levels of the apoptotic factor caspase-3 studied by Western Blotting, Vitamin D3 levels were analyzed using ELISA assay.In the group of children with newly diagnosed T1D an increased rate of dissociation of oxygen and haemoglobin compared to the control group was detected. Children with DN the levels of this index were significantly lower than the control group. We show stage-dependent manner in increase of the cellular hypoxia and apoptotic effector caspase-3 levels. Both markers detected at significantly higher rate in DN patients as compared to T1D. Vitamin-D3 deficiency is documented in patients with DN.Thus, the development of DN in children is associated with violation of Hb/oxygen dissociation, a sign of the high degree of the Hb glycosylation resulting to the formation of cellular hypoxia and activation of apoptosis, as one of the basic mechanisms of cell damage kidneys in DN. All mentioned above disorders accompanied by Vitamin D3 deficiency.

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Molecular mechanisms of diabetic kidney disease

Cited by 722 publications

References 105 publications

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

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

Beyond Proteinuria: Apoptosis and Vitamin D3 State in Children with Diabetic Nephropathy

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