Sarpogrelate hydrochloride ameliorates diabetic nephropathy associated with inhibition of macrophage activity and inflammatory reaction in db/db mice

Lee, Eun Soo; Lee, Mi Young; Kwon, Mi Hye; Kim, Hong Min; Kang, Jin Ku; Kim, You Mi; Lee, Eun Young; Chung, Choon Hee

doi:10.1371/journal.pone.0179221

Cited by 17 publications

(10 citation statements)

References 55 publications

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“…Lemos et al have observed that inhibiting Interleukin-1R (IL-1R) signal transducer kinase IRAK4 (Interleukin-1 receptor-associated kinase 4) can abrogate fibrosis and reduce tubular injury 24 . In our study, the survival rates of NRK-52E and NRK-49F after challenge with LPS were detected and UUO models in mice for 7 days and rats for 4 weeks were established 25,26 . The results showed that in vivo experiments, compared with sham groups, the levels of serum Cr and BUN in UUO animals were significantly increased ( p < 0.05), as well as the histopathological changes.…”

Section: Discussionmentioning

confidence: 72%

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

et al. 2019

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Fatty acid binding protein 4 (FABP4), a subtype of fatty acid-binding protein family, shows critical roles in metabolism and inflammation. However, its roles on regulating renal interstitial fibrosis (RIF) remain unclear. In this work, LPS-stimulated in vitro models on NRK-52E and NRK-49F cells, and in vivo UUO models in rats and mice were established. The results showed that comparing with control groups or sham groups, the expression levels of α-SMA, COL1A, COL3A, IL-1β, IL-6, and TNF-α in LPS-stimulated cells or UUO animals were significantly increased. Meanwhile, the levels of TC, TG, and free fatty acid were also significantly increased as well as the obvious lipid droplets, and the serum levels of BUN, Cr were significantly increased with large amounts of collagen deposition in renal tissues. Further investigation showed that compared with control groups or sham groups, the expression levels of FABP4 in LPS-stimulated cells and UUO animals were significantly increased, resulting in down- regulating the expression levels of PPARγ, upregulating the levels of p65 and ICAM-1, and decreasing the expression levels of ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1. To deeply explore the mechanism of FABP4 in RIF, FABP4 siRNA and inhibitor interfered cell models, and UUO model on FABP4 knockout (KO) mice were used. The results showed that the expression levels of α-SMA, COL1A, and COL3A were significantly decreased, the deposition of lipid droplets decreased, and the contents of TC, TG, and free fatty acids were significantly decreased after gene silencing. Meanwhile, the expression levels of PPAR-γ, ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1 were upregulated, the levels of p65 and ICAM-1 were downregulated, and the mRNA levels of IL-1β, IL-6, and TNF-α were decreased. Our results supported that FABP4 contributed to RIF via promoting inflammation and lipid metabolism, which should be considered as one new drug target to treat RIF.

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Section: Discussionmentioning

confidence: 72%

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

et al. 2019

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“…Reportedly, sarpogrelate also modulates inflammatory-macrophage accumulation and inflammatory responses (36). In a recent experimental study, treatment with sarpogrelate decreased inflammatory macrophage markers and inflammatory mediators in mice with type 2 diabetes and diabetic nephropathy (36). In the present study, combined treatment with sarpogrelate and rosuvastatin resulted in a significant decrease in the mRNA expression levels of inflammatory cytokines levels compared with rosuvastatin alone.…”

Section: Discussionsupporting

confidence: 56%

“…In aortic diseases, hyperlipidemia is a key factor in the development of atherosclerosis as it increases the quantity of circulating inflammatory cells and induces inflammatory pathways (34,35). Reportedly, sarpogrelate also modulates inflammatory-macrophage accumulation and inflammatory responses (36). In a recent experimental study, treatment with sarpogrelate decreased inflammatory macrophage markers and inflammatory mediators in mice with type 2 diabetes and diabetic nephropathy (36).…”

Section: Discussionmentioning

confidence: 99%

Sarpogrelate and rosuvastatin synergistically ameliorate aortic damage induced by hyperlipidemia in apolipoprotein E‑deficient mice

Liu

et al. 2020

Exp Ther Med

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The current study aimed to investigate whether sarpogrelate and rosuvastatin possess anti-arterial injury, and attempted to elucidate the mechanism of action underlying this activity. Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is extensively used to prevent arterial thrombosis; however, its effects on atherosclerosis remain unknown. In the present study, sarpogrelate combined with rosuvastatin or rosuvastatin alone were administered to male ApoE-/mice fed a high-fat diet (HFD) for 8 weeks. Metabolic parameters in the blood samples were analyzed using an automatic analyzer. Aortic tissues were stained with hematoxylin and eosin for morphological analysis. The expression levels of oxidized-low density lipoprotein (LDL) specific scavenging receptors, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 68 were detected via immunostaining. mRNA expression levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were determined via reverse transcription-quantitative PCR analysis, while protein expression levels of LOX-1 and phosphor(p)-ERK were determined via western blot analysis. The results demonstrated that sarpogrelate combined with rosuvastatin treatment significantly decreased total cholesterol and LDL cholesterol levels in the serum, and alleviated intimal hyperplasia and lipid deposition, accompanied by decreased inflammatory cell infiltration and lower expression levels of inflammatory cytokines, compared with rosuvastatin monotherapy or HFD treatment. Furthermore, sarpogrelate combined with rosuvastatin treatment significantly decreased the expression levels of LOX-1 and pERK. Taken together, these results suggest that the positive effects of sarpogrelate combined with rosuvastatin treatment on aortic injury may be associated with the regulation of the LOX-1/p-ERK signaling pathway. Sarpogrelate and rosuvastatin synergistically decreased aortic damage in ApoE-/-HFD mice, and thus provide a basis for the treatment of aortic injury caused by hyperlipidemia with sarpogrelate.

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“…Sarpogrelate decreased immune cell infiltration and NOS2 and TNF expression in diabetic mice. In addition, sarpogrelate inhibited macrophage activation and migration in LPS‐treated Raw264.7 cells . Although the three tested antiplatelet agents displayed anti‐TNF activity in various inflammatory‐related disorders, the present study revealed that compared to each antiplatelet agent, cilostazol is the best option based on its anti‐TNF function.…”

Section: Discussionmentioning

confidence: 61%

Comparative effectiveness of different antiplatelet agents at reducing TNF‐driven inflammatory responses in a mouse model

Lee

Park

Jeong

et al. 2019

Clin Exp Pharma Physio

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Platelets play an important role in the regulation of vascular integrity and haemostasis. However, a massive activation and aggregation of platelets can lead to the formation of an arterial thrombus at the site of an atherosclerotic lesion, subsequently increasing the prevalence of ischaemic diseases. 1 Platelet-mediated inflammatory responses are due to highly potent platelet-derived cytokines and the pleiotropic effect on immune cells, which produce a side effect, namely systemic inflammation. 2 Thus, platelet stimulation and activation are known to contribute to inflammation and vascular injury, as well as the initiation of clot formation. This pathophysiological role of platelets reveals the importance of antiplatelet agents as crucial targets in the antiplatelet therapeutic strategy for patients with cardiovascular disorder.Clopidogrel is an oral antiplatelet agent that hinders blood clots by inhibiting the P2Y2 receptor-induced platelet aggregation.Clopidogrel has been proposed to possess pleiotropic biological AbstractAntiplatelet drugs are conventionally used as treatments because of their anti-coagulation functions. However, their pleiotropic effects are of great significance to the treatment of ischaemic cardiovascular diseases. Many studies have reported that an excessive amount of inflammation driven by tumour necrosis factor (TNF) is closely related to the prevalence of atherosclerosis. As the drug selection criteria and evaluation methods related to the anti-TNF activity of antiplatelet drugs remain limited, our investigation of these drugs should prove beneficial. In this study, we compared the anti-TNF activity of three antiplatelet agents, namely clopidogrel, sarpogrelate, and cilostazol, using the TNF-induced inflammatory mouse model. After the oral administration of these drugs, acute inflammation was induced via injection of lipopolysaccharide (LPS) or D-galactosamine (D-gal) and TNF. Serum TNF levels, and the mRNA and protein expression levels of TNF in mouse heart tissue, macrophage accumulation in aortic lesions, and mouse survival were analysed to compare the anti-TNF effects of the three antiplatelet agents. Of the three antiplatelet agents, cilostazol significantly reduced the different levels under the most effective observation. In addition, cilostazol was found to attenuate the TNF-stimulated phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chainenhancer of activated B cell (NF-κB) p65 in the aortic vascular smooth muscle cell line, MOVAS-1 and the D-gal plus TNF-challenged heart tissue of mouse. Therefore, cilostazol is the most ideal of the three antiplatelet drugs for the treatment of TNFmediated inflammatory disorders. K E Y W O R D S

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Sarpogrelate hydrochloride ameliorates diabetic nephropathy associated with inhibition of macrophage activity and inflammatory reaction in db/db mice

Cited by 17 publications

References 55 publications

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

Sarpogrelate and rosuvastatin synergistically ameliorate aortic damage induced by hyperlipidemia in apolipoprotein E‑deficient mice

Comparative effectiveness of different antiplatelet agents at reducing TNF‐driven inflammatory responses in a mouse model

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