Sodium‐glucose co‐transporters and diabetic nephropathy: Is there a link with toll‐like receptors?

Jigheh, Zahra Ashrafi; Haghjo, Amir Ghorbani; Argani, Hassan; Sanajou, Davoud

doi:10.1111/1440-1681.13261

Cited by 11 publications

(5 citation statements)

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“…GLUT 1 in particular is upregulated in pro-inflammatory macrophages to support the upregulation of glycolytic metabolism ( 48 , 179 ). Macrophages can also accumulate glucose against a concentration gradient in a glucose-deprived environment using sodium-glucose transporters ( 180 , 181 ). However, GLUT 1 is the major transporter of glucose into monocyte/macrophages and is relatively insulin independent, i.e., uptake is determined by the extracellular glucose concentration.…”

Section: Leukocyte Activation In Diabetes—what Is the Evidence?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

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Section: Leukocyte Activation In Diabetes—what Is the Evidence?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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“…However, if AGEs are not metabolized, they deposit in the kidneys and bind to AGE receptors (RAGE), which cause various pathological changes, including oxidative stress, apoptosis, and inflammation ( 35 ). The AGE and RAGE axis play a role in diabetic nephropathy ( 36 , 37 ). In the present study, adding AGE-Tf (33.3 mM) and AGE-Tf (500 mM) to stimulate HK-2 in vitro showed that glycated-Tf promoted apoptosis of HK-2 cells and weakened its antioxidant capacity.…”

Section: Discussionmentioning

confidence: 99%

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

Zhou

Zhao

et al. 2023

Front. Endocrinol.

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Background and objectiveGlycation is a common post-transcriptional modification of proteins. Previous studies have shown that advanced glycation end modified transferrin (AGE-Tf) levels in diabetic rat kidney tissues were increased; however, its role in diabetic nephropathy remains unclear. In this study, differences in glycation degree and Tf sites induced by differing high glucose concentrations in vitro and the effect on total iron binding capacity (TIBC) were observed. Moreover, the effect of AGE-Tf on human renal tubular epithelial cells (HK-2) was investigated.MethodsIn vitro Tf was incubated with increasing glucose concentrations (0 mM, 5.6 mM, 11.1 mM, 33.3 mM, 100 mM, 500 mM, and 1,000 mM) for AGE-Tf. Differences in AGE-Tf glycation degree and TIBC level were analyzed via colorimetric method. The AGE-Tf glycation sites were identified with LC-MS/MS. HK-2 cells were treated with AGE-Tf prepared with different glucose concentrations (33.3 mM and 500 mM) in vitro. The effects of AGE-Tf on HK-2 cell viability, proliferation, oxidative stress index, and Tf receptor expression levels were then observed.ResultsWith increasing glucose concentrations (100 mM, 500 mM, and 1,000 mM) in vitro, Tf glycation degree was significantly increased. The TIBC levels of AGE-Tf were decreased significantly with increasing glucose concentrations (33.3 mM, 100 mM, 500 mM, and 1,000 mM). Four glycated modification sites in Tf and 17 glycated modification sites were detected in AGE-Tf (500 mM) by LC-MS/MS. The structural types of AGEs were CML, G-H1, FL-1H2O, FL, and MG-H1. No significant differences were found in the survival rate of HK-2 cells among the AGE-Tf (500 mM), AGE-Tf (33.3 mM), and Tf groups (all p > 0.05). The apoptosis rate of HK-2 cells in the AGE-Tf (500 mM) group was significantly higher than that in the AGE-Tf (33.3 mM) group. Additionally, both of them were significantly higher than that in the Tf group (both p < 0.05). The MDA levels of HK-2 cells in the AGE-Tf (500 mM) and AGE-Tf (33.3 mM) groups were higher than that in the Tf group, but not significantly (both p > 0.05). The T-AOC level of HK-2 in the AGE-Tf (500 mM) group was significantly lower than that in the AGE-Tf (33.3 mM) and Tf groups (both p < 0.001). The GSH level of HK-2 cells in the AGE-Tf (500 mM) group was significantly lower than that in the Tf group (p < 0.05). The expression level of TfR in the AGE-Tf (500 mM) group was also significantly lower than that in the Tf group (p < 0.05).ConclusionThe degree and sites of Tf glycation were increased in vitro secondary to high-glucose exposure; however, the binding ability of Tf to iron decreased gradually. After HK-2 was stimulated by AGE-Tf in vitro, the apoptosis of cells was increased, antioxidant capacity was decreased, and TfR expression levels were downregulated.

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“…Advanced glycation end-products (AGEs) are heterogeneous compounds that are created when proteins, lipids, or nucleic acids are glycated during hyperglycemia without the use of an enzyme. A novel risk factor for the development of DN has been discovered: the buildup of AGEs in peripheral nerves [ 24 ]. The gold standard for AGE assessments in tissues is tissue biopsy.…”

Section: Reviewmentioning

confidence: 99%

A Narrative Review of New Treatment Options for Diabetic Nephropathy

Pillai¹,

Fulmali²

2023

Cureus

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Diabetic nephropathy (DN) is a type of nephropathy that is caused by a diabetic condition. Diabetic nephropathy is seen in type 1 and type 2 diabetes. End-stage renal disorders are brought on by DN. Diabetic nephropathy is thought to be linked to metabolic changes in the body. Proteinuria and glomerular filtration rate are the two most crucial diagnostic and prognosis measures for diabetic kidney disease (DKD), yet both have significant disadvantages. Novel biomarkers are thus increasingly required to improve risk factors and detect disease at an early stage. Controlling blood glucose and vital sign like body temperature and blood pressure, reducing cholesterol levels, and blocking the renin-angiotensin system are the standard treatments for diabetic patients. On the other hand, if used too late within the course of the disease, these therapeutic techniques can only provide partial relief from nephropathy.The complicated pathophysiology of the diabetic kidney, which experiences a variety of severe structural, metabolic, and functional alterations, represents one of the most important obstacles to the event of effective therapeutics for DN. Despite these issues, new diabetes models have identified promising treatment targets by identifying the mechanisms that control important functions of podocytes and glomerular endothelial cells. It has been shown in the vast majority of trials that renin-angiotensin system inhibitors combined with integrative therapies work well for DN. Combining sodium-glucose cotransporter-2 inhibitors and renin-angiotensin-aldosterone system blockers is a novel way to slow down the course of DKD by lowering inflammatory and fibrotic indicators brought on by hyperglycemia, which is more effective than using either medicine alone. Aldosterone receptor inhibitors and advanced glycation end-product inhibitors are two recently produced medications that may be used successfully to treat DN.

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Sodium‐glucose co‐transporters and diabetic nephropathy: Is there a link with toll‐like receptors?

Cited by 11 publications

References 73 publications

The Role of Inflammation in Diabetic Retinopathy

The Role of Inflammation in Diabetic Retinopathy

Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro

A Narrative Review of New Treatment Options for Diabetic Nephropathy

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