Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways
Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways
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DOI：
10.1016/j.ejphar.2020.173010
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发表时间：
2020-05-05
影响因子：
5
通讯作者：
El-Abhar, Hanan S.
中科院分区：
文献类型：
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作者：
El-Nasr, Nesma M. E. Abo;Saleh, Dalia Osama;El-Abhar, Hanan S.
Olmesartan （OLM）是一种血管紧张素受体阻滞剂，对与肾/心血管并发症相关的糖尿病/胰岛素抵抗（IR）模型进行了测试。方法：采用高脂/高果糖饮食7周+单次亚糖尿病剂量链脲佐菌素（35mg/kg; i.p）诱导的IR/ 2型糖尿病（IR/D）模型，检测其对糖尿病诱导的肝栓的潜在作用。IR/D大鼠口服OLM （10 mg/kg）、吡格列酮（PIO； 5或10 mg/kg）或其联合治疗，连续4周。OLM单独反对IR/D的有害影响；OLM可显著改善代谢参数、肝功能、减轻肝脏氧化应激、炎症细胞因子白介素-6 （IL-6）及其上游介质核因子kappa b。因此，OLM可关闭下游线索p-Jak2/STAT3/SOCS3。此外，它抑制升高的AGE/RAGE/p-JNK通路，增加PPAR γ /脂联素提示其抗炎和抗氧化能力（GSH， MDA）。然而，OLM与PIO的联合用药显示出上述所有参数以剂量依赖的方式协同改善。此外，具有PIO10的OLM引起肝脏PPARy和脂联素的激增（5倍和6倍），NF-kappa B/IL-6/p-STAT3/SCOS3通路急剧下降约85%。组织病理学研究证实了这些作用。综上所述，OLM及其联合PIO可能通过调节多种相互关联的通路来增强胰岛素敏感性并预防2型糖尿病相关的肝脏并发症；即代谢改变，肾素-血管紧张素系统，炎症轨迹，以及氧化应激。本研究表明OLM作为常规降糖治疗的辅助治疗具有潜在的协同作用。
Olmesartan (OLM), an angiotensin receptor blocker, was tested against diabetes/insulin resistance (IR) models associated with renal/cardiovascular complications. Methods: we tested its potential role against diabetes-induced hepatic hitches using an IR/type2 diabetic (IR/D) model induced by high fat/high fructose diet for 7 weeks + a single sub-diabetogenic dose of streptozotocin (35mg/kg; i.p). IR/D rats were orally treated with OLM (10 mg/kg), pioglitazone (PIO; 5 or 10 mg/kg) or their combinations for 4 consecutive weeks. OLM alone opposed the detrimental effects of IR/D; it significantly improved metabolic parameters, liver function, and abated hepatic oxidative stress, and inflammatory cytokine interleukin-6 (IL-6) and its upstream mediator nuclear factor kappa B. Consequently, OLM turned off the downstream cue p-Jak2/STAT3/SOCS3. Moreover, it suppressed the elevated AGE/RAGE/p-JNK pathway and increased the PPAR gamma/adiponectin cue to signify its anti-inflammatory and anti-oxidant capacity (GSH, MDA). Nevertheless, co-administration of OLM to PIO showed a synergistic improvement in all the aforementioned parameters in a dose dependent manner. Additionally, OLM with PIO10 provoked a surge in hepatic PPARy and adiponectin (5 and 6 folds) with a sharp decrease of about 85% in the NF-kappa B/IL-6/p-STAT3/SCOS3 pathway. These effects were confirmed by the histopathological study. In conclusion, OLM and its combination with PIO enhanced insulin sensitivity and guarded against hepatic complications associated with type 2 diabetes probably via modulating various inter-related pathways; namely, metabolic alteration, renin-angiotensin system, inflammatory trajectories, as well as oxidative stress. This study manifests the potential synergistic effects of OLM as an adjuvant therapy to the conventional antidiabetic therapies.