Ursolic acid reduces inflammation and fibrosis in the kidney of diabetic mice

熊果酸 糖尿病肾病 纤维化 炎症 糖尿病 尾加压素Ⅱ 医学 内科学 肾小球硬化 肾脏疾病 链脲佐菌素 内分泌学 药理学 足细胞 化学 蛋白尿 受体 色谱法
作者
SA Manea,AG Lazar,ML Vlad,Andrei Manea
出处
期刊:Cardiovascular Research [Oxford University Press]
卷期号:118 (Supplement_1)
标识
DOI:10.1093/cvr/cvac066.225
摘要

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UEFISCDI Background Diabetic kidney disease (DKD) is arguably the major disabling and life-threatening microvascular-related disorder associated with both type I and type II diabetes. Inflammation of glomerular capillary system and progressive accumulation of glomerular extracellular proteins are important culprit mechanisms leading to glomerulosclerosis and ultimately renal failure in end-stage DKD. Conventional anti-diabetic therapies can only delay the progression of DKD. The naturally-occurring triterpenic acids emerged as important candidate pharmacological compounds for the treatment of cardiometabolic disorders. Purpose We aimed at investigating the potential regulatory effects of ursolic acid, a pentacyclic triterpenoid, on the expression of key pro-inflammatory and pro-fibrotic mediators in diabetic kidney. Methods Non-diabetic and streptozotocin-induced diabetic C57BL/6J male mice were randomized to receive via intraperitoneal injection 1 mg/kg ursolic acid (UA), or its vehicle (5% DMSO + 95% PBS, pH 7.4), for 4 weeks. Human endothelial cells (EC) were exposed to normal (5 mM) or high (25mM) concentration of glucose in the absence/presence of 1-10 μM UA. Real-time PCR, Western blot, and immunofluorescence microscopy techniques were employed to investigate the expression of selected DKD-relevant pro-inflammatory and pro-fibrotic molecules. Morphological aspects of the kidney and glomeruli were assessed by histochemistry. Results The mRNA/protein levels of pro-inflammatory (MCP-1, TNFα, NOS2, ICAM-1, VCAM-1, E-selectin) and pro-fibrotic (collagen IV, fibronectin, laminin, TGFβ) mediators were found significantly elevated in the kidney of diabetic mice as compared to non-diabetic counterparts. Treatment of diabetic mice with UA significantly reduced the up-regulated expression of pro-inflammatory mediators, extracellular matrix proteins, and pro-fibrotic factor TGFβ. Moreover, glomerular hypertrophy and the up-regulation of glomerular collagen IV, fibronectin, and laminin protein levels were significantly reduced in UA-treated diabetic mice. In cultured human EC, UA suppressed the high glucose-induced up-regulation of ICAM-1, VCAM-1, E-selectin and NF-kB signaling. Conclusion In experimental diabetes, ursolic acid down-regulates the expression of DKD-relevant pro-inflammatory and pro-fibrotic molecules in the kidney of diabetic mice by potentially targeting NF-kB signaling pathway. The data of this study suggest that triterpenic acids and their chemical derivates could become important pharmacological tools to reduce inflammation and fibrosis associated with DKD.

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