Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice

Yin, Qudong; Zhang, Rui; Li, Li; Wang, Yiting; Liu, Jingping; Zhang, Jie; Bai, Lin; Cheng, Jun; Fu, Ping; Liu, Fang

doi:10.1074/jbc.m116.730564

Cited by 56 publications

(42 citation statements)

References 65 publications

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“…Ex-4 and sitaglitin (DPP4 inhibitor) are known to improve kidney function by attenuating inflammation in chronic or diabetic kidney disease models. 17,72 Therefore, it is unclear whether the beneficial effect of Ex-4 is due to its role in improving kidney function, its direct effect on muscle, or both in the current study. Further studies are needed to clarify this.…”

Section: Discussionmentioning

confidence: 79%

“…Similar to the observations in Dex‐treated mice, Ex‐4 significantly increased total muscle mass, CSA of the TA muscle, and muscle function in CKD mice. Ex‐4 and sitaglitin (DPP4 inhibitor) are known to improve kidney function by attenuating inflammation in chronic or diabetic kidney disease models . Therefore, it is unclear whether the beneficial effect of Ex‐4 is due to its role in improving kidney function, its direct effect on muscle, or both in the current study.…”

Section: Discussionmentioning

confidence: 82%

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Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

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Background Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved. Methods Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model. Results Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (MuRF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice. Conclusions GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 82%

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

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“…The extensive change of pathological procedure contributed to DN, within which leukocyte-EC adhesion and EC inflammation exacerbated glomerular EC injury. [45][46][47][48][49] Hence, reducing leukocyte-EC adhesion and EC inflammation are promising therapeutic tactics to alleviate DN. ICAM-1 is a member of the CAM superfamily and plays an important effect in mediating the migration of leukocytes to pass through the endothelium and enter the kidneys.…”

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confidence: 99%

Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium

Tong¹,

Liu²,

Yan³

et al. 2017

IJN

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The purpose of the study was to reveal the therapeutic effect of quercetin (QUE) nanoparticle complex on diabetic nephropathy (DN) by regulating the expression of intercellular adhesion molecular-1 (ICAM-1) on endothelium as compared to free QUE. QUE 10 mg/kg as a single abdominal subcutaneous injection daily for 8 weeks continuously in diabetic rats and 10 mg/kg QUE nanoparticle complex as a single abdominal subcutaneous injection every 5 days, continuously administered for 8 weeks to diabetic rats. Blood and left kidneys were collected; pathological change of kidney, renal function, oxidative stress level, blood glucose level, serum lipid, urine protein, and albumin/creatinine ratio were measured; and neutrophil adhesion, ICAM-1 expression, and CD11b + cells infiltration were observed. Both QUE and QUE nanoparticle complex preconditioning ameliorated the pathological damage of kidney and improved renal function, alleviated renal oxidative stress injury, restricted inflammatory cells infiltration, and downregulated the ICAM-1 expression as compared to DN group, while QUE nanoparticle complex significantly alleviated this effect.

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“…These effects were accompanied by downregulation of TGFB1 expression, decreased collagen type IV accumulation, suppressed inflammation, reduced apoptosis and lower oxidative stress (Park et al 2007). In alignment with these findings, many other studies also revealed renal beneficial effects of GLP-1 analogues in animal models of diabetic nephropathy suggesting many mechanisms behind these effects such as cAMPprotein kinase A pathway activation, inhibition of renal NAD(P)H oxidases (Hendarto et al 2012, Fujita et al 2014a, downregulation of AGE-induced protein arginine methyltranferase-1 expression (Ojima et al 2013), decreased ICAM-1 production, reduced release of proinflammatory cytokines from macrophages (Kodera et al 2011) and up-regulation of ATP-binding cassette transporter A1 (ABCA1) in glomerular endothelial cells, which promoted cholesterol efflux from cells and blocked inflammatory responses (Yin et al 2016). Moreover, the natriuretic and diuretic effects of GLP-1 analogues and DPP-4 inhibitors through interaction with Na + /H + exchanger isoform 3 could play a role regarding their reno-protective effects.…”

Section: Glp-1mentioning

confidence: 99%

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

Hasan

Hocher

2017

Journal of Molecular Endocrinology

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Diabetic nephropathy is one of the most frequent, devastating and costly complications of diabetes. The available therapeutic approaches are limited. Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent a new class of glucose-lowering drugs that might also have reno-protective properties. DPP-4 exists in two forms: a plasma membranebound form and a soluble form, and can exert many biological actions mainly through its peptidase activity and interaction with extracellular matrix components. The kidneys have the highest DPP-4 expression level in mammalians. DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. Preclinical animal studies and some clinical data suggest that DPP-4 inhibitors decrease the progression of diabetic nephropathy in a blood pressure-and glucose-independent manner. Many studies reported that these reno-protective effects could be due to increased half-life of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1 alpha (SDF-1a). However, the underlying mechanisms are far from being completely understood and clearly need further investigations.

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Exendin-4 Ameliorates Lipotoxicity-induced Glomerular Endothelial Cell Injury by Improving ABC Transporter A1-mediated Cholesterol Efflux in Diabetic apoE Knockout Mice

Abstract: Edited by Dennis VoelkerATP

Cited by 56 publications

References 65 publications

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

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