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大麻素受体 2 (CB2) 激动剂和 L-精氨酸通过 NF-κβ 通路抑制炎症和纤维化,改善大鼠糖尿病肾病
Naunyn-Schmiedeberg's Archives of Pharmacology
(
IF
3.1
)
Pub Date : 2023-07-14
, DOI:
10.1007/s00210-023-02597-0
Vivek S Kumawat
1
,
Ginpreet Kaur
1
Affiliation
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
糖尿病肾病 (DN) 是一种导致终末期慢性肾病的疾病,其特征是炎症和一氧化氮 (NO) 缺乏。特定激动剂激活大麻素受体 (CB 2 ) 会降低核因子 kappa beta (NF-κβ) 的表达。 Beta caryophyllene (BCP) 是一种天然 CB 2受体激活剂,可在多种疾病中保护肾功能。 l-精氨酸 (LA) 通过提供一氧化氮 (NO) 来调节多种生理过程。因此,我们测试了一种新型 BCP-LA 组合来治疗 DN,并研究了其分子机制。在 SD 大鼠中,对 BCP、LA 以及两者的组合在 LPS 诱导的 RAW 264.7 巨噬细胞炎症以及链脲佐菌素 (55 mg/kg) 诱导的糖尿病中进行了评估。糖尿病大鼠口服 200 mg/kg BCP、100 mg/kg LA 以及两者的组合,持续 28 天。评估血浆中的生化标志物和炎症细胞因子;此外,还检查了肾组织的肾氧化应激损伤、NF-κβ 表达和组织学。治疗28天后,BCP和LA组合较疾病对照组显着降低血糖水平。 BCP 和 LA 还能使糖尿病大鼠的肾脏标志物和氧化应激正常化。血浆和 RAW 巨噬细胞系显示 IL-6 和 TNF-α 水平降低( P < 0.001)。组织病理学评估显示,BCP 和 LA 共同减少肾纤维化,胶原沉积也改善肾病指数。同时,BCP和LA共同作用可显着降低糖尿病大鼠的NF-κβ( P < 0.01)。 这些结果表明,创新方案 BCP 与 LA 可能是 DN 的一种治疗方法,因为它通过抑制 NF-κβ 来保护肾组织免受糖尿病的影响。
图形概要
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Cannabinoid receptor 2 (CB2) agonists and l-arginine ameliorate diabetic nephropathy in rats by suppressing inflammation and fibrosis through NF-κβ pathway
Diabetic nephropathy (DN) is a condition that leads to end-stage chronic kidney disease characterized by inflammation and a deficiency of nitric oxide (NO). Cannabinoid receptor (CB2) activation by specific agonist reduces nuclear factor kappa beta (NF-κβ) expression. Beta caryophyllene (BCP), a natural CB2 receptor activator, protects kidney function in several diseases. l-Arginine (LA) modulates several physiological processes by donating nitric oxide (NO). Hence, we tested a novel BCP-LA combination to treat DN and investigated its molecular mechanisms. BCP, LA, and combinations of both were evaluated in LPS-induced RAW 264.7 macrophage inflammation as well as in streptozotocin (55 mg/kg)-induced diabetes in SD rats. Diabetic rats were administered 200 mg/kg of BCP, 100 mg/kg of LA, and combination of both orally for 28 days. Biochemical markers and inflammatory cytokines were assessed in plasma; also, kidney tissue was examined for renal oxidative stress injury, NF-κβ expression, and histology. After 28 days of treatment, BCP and LA combination significantly lowered plasma glucose levels than the disease control group. BCP and LA also normalized renal markers and oxidative stress of diabetic rats. Plasma and RAW macrophage cell lines showed reduced levels of IL-6 and TNF-α (P < 0.001). Histopathological evaluations revealed that BCP and LA together decreased renal fibrosis and collagen deposition also improved nephrotic indices. Meanwhile, the effect of BCP and LA together significantly reduced the NF-κβ (P < 0.01) against diabetic rats. These results indicate that the innovative regimen BCP with LA may be a therapeutic treatment for DN, as it protects kidney tissue from diabetes via NF-κβ inhibition.
Graphical abstract
更新日期:2023-07-14