The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis

Li, Yakun; Ma, Dongxia; Wang, Zhimin; Hu, Xiaofan; Li, Shang-Lin; Tian, Hongzhe; Wang, Mengjun; Shu, Yan-Wen; Yang, Jun

doi:10.1016/j.phrs.2018.03.004

Cited by 63 publications

(55 citation statements)

References 41 publications

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“…For instance, exendin-4 has been shown to ameliorate the high glucose-induced fibronectin (FN) and type I collagen (Col1) expression in tubular epithelial cells by inhibiting the secretion of miR-192, an microRNA (miRNA) that is regulated by p53 and plays a role in renal fibrosis (Jia et al, 2018). Consistent with this observation, liraglutide has been shown to attenuate unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis by suppressing TGF-b and its downstream signaling pathways, including Smad3 and ERK1/2 (Li et al, 2018). These protective effects of GLP-1RAs for renal fibrosis are also mediated by attenuating the epithelial-to-mesenchymal transition (EMT) of tubular cells (Li et al, 2018;Yin et al, 2018).…”

Section: Natriuresismentioning

confidence: 81%

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

Kawanami

Yuasa

2020

Front. Pharmacol.

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Diabetic Kidney Disease (DKD) is the leading cause of end stage renal disease (ESRD) worldwide. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are now widely used in the treatment of patients with type 2 diabetes (T2D). A series of clinical and experimental studies demonstrated that GLP-1RAs have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by natriuresis, antiinflammatory and anti-oxidative stress properties. Furthermore, GLP-1RAs have been shown to suppress renal fibrosis. Recent clinical trials have demonstrated that GLP-1RAs have beneficial effects on renal outcomes, especially in patients with T2D who are at high risk for CVD. These findings suggest that GLP-1RAs hold great promise in preventing the onset and progression of DKD. However, GLP-1RAs have only been shown to reduce albuminuria, and their ability to reduce progression to ESRD remains to be elucidated. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying the effects of GLP-1RAs in DKD.

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Section: Natriuresismentioning

confidence: 81%

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

Kawanami

Yuasa

2020

Front. Pharmacol.

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“…Several basic and clinical studies have demonstrated that treatment with GLP-1 analogs or GLP-1R agonists greatly mitigates renal fibrosis associated with DN by inhibiting TGF-β1-activated Smad 3 and ERK1/2 [ 39 ]. Furthermore, GLP-1-activated cyclic AMP-protein kinase A is thought to increase Sirt-1 activity through phosphorylation of Sirt-1 (serine 434) [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Huang

Chou

2020

Nutrients

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Fucoidan extracted from brown algae has multiple beneficial functions. In this study, we investigated the effects of low-molecular-weight fucoidan (oligo-FO) on renal fibrosis under in vitro and in vivo diabetic conditions, and its molecular mechanisms. Advanced glycation product (AGE)-stimulated rat renal proximal tubular epithelial cells (NRK-52E) and diabetic mice induced by high-fat diet and intraperitoneal injection of streptozotocin and nicotinamide were used. Oligo-FO treatment significantly inhibited anti-high mobility group box 1 (HMGB1)/RAGE/ anti-nuclear factor-kappa B (NF-κB)/transforming growth factor-β1 (TGF-β1)/TGF-β1R/Smad 2/3/fibronectin signaling pathway and HIF-1α activation in AGE-stimulated NRK-52E cells. Conversely, the expression and activity of Sirt-1; the levels of ubiquitin-specific peptidase 22 (USP22), p-AMPK, glucagon-like peptide-1 receptor (GLP-1R), and heme oxygenase-1 (HO-1); and Nrf2 activation were remarkably increased by oligo-FO in AGE-stimulated cells. However, the above effects of oligo-FO were greatly diminished by inhibiting Sirt-1, HO-1, or GLP-1R activity. Similar changes of these pro-fibrotic genes in the kidney and a marked attenuation of renal injury and dysfunction were observed in oligo-FO-treated diabetic mice. These findings indicated that the inhibitory effects of the oligo-FO on diabetes-evoked renal fibrosis are mediated by suppressing TGF-β1-activated pro-fibrogenic processes via Sirt-1, HO-1, and GLP-1R dependence. Collectively, fucoidan-containing foods or supplements may be potential agents for ameliorating renal diseases due to excessive fibrosis.

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“…Activation of the GLP-1R/cAMP/PKA pathway is also crucial in renal protection, with studies in a range of rodent models reporting a reduction in renal inflammation, renal fibrosis, and decrease in renal oxidative stress arising from the toxic milieu induced in metabolic syndrome ( 158 , 161 , 166 , 177 , 178 ). These pro-survival abilities are believed to arise from enhanced GLP-1 signaling leading to a reduced expression of the pro apoptotic markers caspase-3, and Bax/Bcl-2 ( 158 ), as well as reducing oxidative stress through increased expression of the oxidative defense gene heme oxygenease-1 (HO-1) ( 160 , 178 ), and inhibition of NAD(P)H oxidase in a cAMP/PKA dependent manner ( 166 ).…”

Section: Glp-1 Action In Other Tissuesmentioning

confidence: 99%

“…These pro-survival abilities are believed to arise from enhanced GLP-1 signaling leading to a reduced expression of the pro apoptotic markers caspase-3, and Bax/Bcl-2 ( 158 ), as well as reducing oxidative stress through increased expression of the oxidative defense gene heme oxygenease-1 (HO-1) ( 160 , 178 ), and inhibition of NAD(P)H oxidase in a cAMP/PKA dependent manner ( 166 ). Activation of the GLP-1R signaling pathway has also been reported to reduce macrophage infiltration, potentially alleviating the associated increase in ROS and inflammation, as well as attenuating the progression of renal fibrosis through downregulation of ERK1/2 and its upstream activator transforming growth factor-beta 1 (TGF-β1) ( 160 , 177 ). Despite these results, further studies are still required to fully elucidate the molecular mechanisms that mediate the reported attenuation in apoptotic and inflammatory pathways, particularly as accumulating clinical evidence highlights the potential of GLP-1R agonist therapies in DKD, ultimately urging for deeper understanding of cellular actions of these analogs in the renal tissue [reviewed in ( 156 , 157 , 159 , 162 , 179 )].…”

Section: Glp-1 Action In Other Tissuesmentioning

confidence: 99%

Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function

et al. 2018

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The incretin hormone Glucagon-Like Peptide-1 (GLP-1) is best known for its “incretin effect” in restoring glucose homeostasis in diabetics, however, it is now apparent that it has a broader range of physiological effects in the body. Both in vitro and in vivo studies have demonstrated that GLP-1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic reprogramming, stimulate anti-inflammatory signaling, alter gene expression, and influence neuroprotective pathways. A substantial body of evidence has accumulated with respect to how GLP-1 and its analogs act to restore and maintain normal cellular functions. These findings have prompted several clinical trials which have reported GLP-1 analogs improve cardiac function, restore lung function and reduce mortality in patients with obstructive lung disease, influence blood pressure and lipid storage, and even prevent synaptic loss and neurodegeneration. Mechanistically, GLP-1 elicits its effects via acute elevation in cAMP levels, and subsequent protein kinase(s) activation, pathways well-defined in pancreatic β-cells which stimulate insulin secretion in conjunction with elevated Ca2+ and ATP. More recently, new studies have shed light on additional downstream pathways stimulated by chronic GLP-1 exposure, findings which have direct relevance to our understanding of the potential therapeutic effects of longer lasting analogs recently developed for clinical use. In this review, we provide a comprehensive description of the diverse roles for GLP-1 across multiple tissues, describe downstream pathways stimulated by acute and chronic exposure, and discuss novel pleiotropic applications of GLP-1 mimetics in the treatment of human disease.

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The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal fibrosis

Cited by 63 publications

References 41 publications

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function

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