Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells

Xu, Chenke; Wang, Wei; Zhong, Jin; Fan, Lei; Xu, Ning; Zhang, Yaou; Xie, Weidong

doi:10.1016/j.bcp.2018.03.013

Cited by 125 publications

(99 citation statements)

References 33 publications

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“…In the previous studies, empagliflozin restored autophagy in the tubular cells in a model of streptozotocin-induced diabetes [20], and in the heart in a model of myocardial infarction and type 2 diabetes [58]. Canagliflozin, another SGLT2 inhibitor, activated autophagy in immune cells [29]. A negative correlation between beclin-1 and DPP4 activity was observed in patients with coronary heart disease [59].…”

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 88%

“…Accordingly, LC3-II is relatively specifically associated with autophagosomes and autolysosomes [28]. In previous studies, both a decrease in LC3-II/LC3-I ratio [29,30] and an increase in LC3-I/II expression [31] in the kidneys of db/db mice was reported. In podocyte cell culture, the expression of LC3-II was increased under high glucose condition [32].…”

Section: Suppression Of Renal Autophagy In Diabetes: Markers and Mechmentioning

confidence: 89%

“…In the liver of ob/ob mice, sitagliptin increased the levels of phosphorylation of AMPK and decreased those of mTOR [62]. The activation of the AMPK signaling pathway in immune cells was proven for canagliflozin [29]. Further identification of the molecular mechanisms for autophagy activation under SGLT2 and DPP4 inhibition is a challenge for future research.…”

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 99%

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SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Korbut

Taskaeva

Bgatova

et al. 2020

IJMS

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Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin-linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin-linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes.Int. J. Mol. Sci. 2020, 21, 2987 2 of 22 dedifferentiation. In its turn, the loss or damage of podocytes causes dysfunction of the filtration barrier and increases albuminuria [2]. Some recent studies have indicated an emerging role of autophagy downregulation in diabetic podocytopathy [4][5][6]. Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins [6]. The process is vital for highly differentiated post-mitotic cells, such as neurons and podocytes [7]. A growing body of evidence indicates a critical role of autophagy in maintaining podocyte integrity and renal function [6]. Mice with podocyte-specific deletion of autophagic regulators, such as class III PI3K vacuolar protein sorting 34 (Vps34) and the Atg5 gene, develop early proteinuria, progressive glomerulosclerosis, and renal failure [6]. Accordingly, autophagy is considered a potential therapeutic target for renal protection [8,9].Sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidylpeptidase-4 (DPP4) inhibitors are promising antidiabetic agents introduced into clinical practice in the last decade. The antihyperglycemic effect of SGLT2 inhibitors is mediated by increment of glucosuria, while DPP4 inhibitors realize their activity through an increase in the half-life of incretin hormones. Both SGLT2 and DPP4 inhibitors demonstrated renal protective...

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Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 88%

Section: Suppression Of Renal Autophagy In Diabetes: Markers and Mechmentioning

confidence: 89%

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 99%

See 1 more Smart Citation

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Korbut

Taskaeva

Bgatova

et al. 2020

IJMS

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“…Attenuation/inhibition of atherosclerosis in our model is mainly attributed to the glucose and lipid-lowering effects of canagliflozin. Correlation analysis showed that the atherosclerotic area is related to glucose and LDLcholesterol range after the intervention; however, direct effects of canagliflozin could not be ruled out especially in the light of recent studies demonstrating direct effects of canagliflozin on human endothelial cells and monocyte/ macrophages, both involved in atherogenesis process [9,10]. Of note, SGLT2 is not detected at mRNA level in human endothelial cells, while it remains uncertain if SGLT2 protein is present [9].…”

Section: Discussionmentioning

confidence: 99%

Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice

Dimitriadis¹,

Nasiri-Ansari²,

Agorogiannis³

et al. 2018

EJEA

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Background: Sodium glucose co-transporter2 inhibitors reduce the incidence of cardiovascular events in patients with type 2 diabetes mellitus based on the results of recent cardiovascular outcome studies. Herein, we investigated the effects of long-term treatment with canagliflozin on biochemical and immunohistochemical markers related to atherosclerosis and atherosclerosis development in the aorta of apolipoprotein E knockout (Apo-E (−/−)) mice. Methods: At the age of 5 weeks, mice were switched from normal to a high-fat diet. After 5 weeks, Apo-E (−/−) mice were divided into control-group (6 mice) treated with 0.5% hydroxypropyl methylcellulose and Cana-group (7 mice) treated with canagliflozin (10 mg/kg per day) per os. After 5 weeks of intervention, animals were sacrificed, and heart and aorta were removed. Sections stained with hematoxylin-eosin (H&E) were used for histomorphometry whereas Masson's stained tissues were used to quantify the collagen content. Immunohistochemistry to assess MCP-1, CD68, a-smooth muscle actin, MMP-2, MMP-9, TIMP-1 and TIMP-2 expression was carried out and q-PCR experiments were performed to quantify mRNA expression. Results: Canagliflozin-group mice had lower total-cholesterol, triglycerides and glucose levels (P < 0.01), while heart rate was significantly lower (P < 0.05). Histomorphometry revealed that one in seven Cana-group mice versus four in six control mice developed atheromatosis, while aortic root plaque was significantly less, and collagen was 1.6 times more intense in canagliflozin-group suggesting increased plaque stability. Immunohistochemistry revealed that MCP-1 was significantly less expressed (P < 0.05) in the aortic root of canagliflozin-group while reduced expression of a-actin and CD68 was not reaching significance (P = 0.15). VCAM-1 and MCP-1 mRNA levels were lower (P = 0.02 and P = 0.07, respectively), while TIMP-1/MMP-2 ratio expression was higher in canagliflozin-group approaching statistical significance (P = 0.07). Conclusions: Canagliflozin attenuates the progression of atherosclerosis, reducing (1) hyperlipidemia and hyperglycemia, and (2) inflammatory process, by lowering the expression of inflammatory molecules such as MCP-1 and VCAM-1. Moreover, canagliflozin was found to increase the atherosclerotic plaque stability via increasing TIMP-1/ MMP-2 ratio expression.

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“…Similarly, ipragliflozin treatment induces healthy adipose tissue expansion and decreases the M1‐like/M2‐like ratio of ATMs in HFD‐fed mice in conjunction with improvements in hyperglycemia and hyperinsulinemia . Xu et al were the first to demonstrate that canagliflozin treatment markedly suppresses the inflammatory response in LPS‐induced mouse and human immune cells via reductions in intracellular glycolysis and enhancements in autophagy. Moreover, reductions in obesity‐induced IR and excess fat accumulation are observed when canagliflozin or tofogliflozin are administered .…”

Section: Novel Antidiabetic Drugs Provide New Therapeutic Perspectivementioning

confidence: 99%

Adipose Tissue Macrophage Phenotypes and Characteristics: The Key to Insulin Resistance in Obesity and Metabolic Disorders

Ota

Zhuge

et al. 2020

Obesity

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Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells

Cited by 125 publications

References 33 publications

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice

Adipose Tissue Macrophage Phenotypes and Characteristics: The Key to Insulin Resistance in Obesity and Metabolic Disorders

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