Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease
Ectopic lipid accumulation: potential role in tubular injury and inflammation in diabetic kidney disease
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异位脂质积累：在糖尿病肾病肾小管损伤和炎症中的潜在作用。
DOI：
10.1042/cs20180702
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发表时间：
2018-11-30
期刊：
影响因子：
6
通讯作者：
Xiao, Li
中科院分区：
文献类型：
--
作者：
Yang, Wenxia;Luo, Ying;Xiao, Li
新的研究表明，脂质在糖尿病肾病（DKD）期间在肾脏中积聚。然而，异位脂质积聚与肾小管损伤之间的相关性迄今尚未完全阐明。使用油红染色，与对照组相比，在2型DKD患者（III-III类）和db/db小鼠的肾脏中观察到脂质蓄积，主要位于近端肾小管室。免疫组化（IHC）染色显示脂肪分化相关蛋白（ADRP）和固醇调节元件结合蛋白-1（SREBP-1）表达明显上调，且与肾小管间质损伤评分和炎症反应呈正相关。DKD患者尿ADRP含量显著高于对照组，且与血脂代谢异常、血肌酐、尿N-乙酰-β-氨基葡萄糖苷酶（NAG）、白蛋白排泄（白蛋白/肌酐比值（ACR））、肿瘤坏死因子-α（TNF-α）表达呈正相关。然而，血浆ADRP水平没有观察到显着差异。此外，从DKD患者分离的外周血单个核细胞（PBMC）中SREBP-1蛋白的表达显著增加，这也与尿NAG、ACR和TNF-α水平密切相关。体外研究表明，在高糖（HG）培养的HK-2细胞中，ADRP和SREBP-1表达增加，伴随着脂质积聚。HG诱导高水平的TNF-α表达，其被ADRP siRNA或SREBP-1 siRNA转染部分阻断。这些数据表明，ADRP和SREBP-1是介导脂质积聚与肾小管损伤和炎症的DKD的关键因素，并且异位脂质积聚可作为改善DKD肾小管损伤的新的治疗靶点。
Emerging studies suggest that lipid accumulates in the kidneys during diabetic kidney disease (DKD). However, the correlation between ectopic lipid accumulation with tubular damage has not been thoroughly elucidated to date. Using Oil Red staining, lipid accumulation was observed in the kidneys of type 2 DKD patients (classes III-III) and db/db mice compared with the control and was predominantly located in the proximal tubular compartment. Immunohistochemistry (IHC) staining showed that the intensity of adipose differentiation related protein (ADRP) and sterol regulatory element binding protein-1 (SREBP-1) was clearly up-regulated, which was positively correlated with the tubulointerstitial damage score and inflammation. Furthermore, the urine ADRP content significantly increased in DKD patients compared with the control, which positively correlated with abnormal lipid metabolism, serum creatinine, urine N-acetyl- beta-glucosaminidase (NAG), albumin excretion (albumin-to-creatinine ratio (ACR)), and tumor necrosis factor-alpha (TNF-alpha) expression. However, there was no significant difference observed in plasma ADRP levels. In addition, the expression of SREBP-1 protein was dramatically increased in peripheral blood mononuclear cells (PBMCs) isolated from DKD patients, which was also tightly correlated with urine NAG, ACR, and TNF-alpha levels. In vitro studies demonstrated increased ADRP and SREBP-1 expression accompanied by lipid accumulation in HK-2 cells cultured in high glucose (HG). HG induced high levels of TNF-alpha expression, which was partially blocked by transfection of ADRP siRNA or SREBP-1 siRNA. These data indicated that ADRP and SREBP-1 are crucial factors that mediate lipid accumulation with tubular damage and inflammation in DKD, and ectopic lipid accumulation may serve as a novel therapeutic target for amelioration of tubular injury in DKD.