Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention
Renal tubule ectopic lipid deposition in diabetic kidney disease rat model and in vitro mechanism of leptin intervention
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DOI：
10.1007/s13105-022-00874-9
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发表时间：
2022-02
影响因子：
3.4
通讯作者：
Shasha Liu;J. Da;Jiali Yu;R. Dong;Jing Yuan;Fuxun Yu;Y. Zha
中科院分区：
文献类型：
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作者：
Shasha Liu;J. Da;Jiali Yu;R. Dong;Jing Yuan;Fuxun Yu;Y. Zha
糖尿病肾病（DKD）是与脂质代谢紊乱密切相关的重大健康负担。瘦素具有降脂作用，但其对肾脏局部作用的具体机制尚不清楚。本研究旨在探讨异位脂质沉积（ELD）在DKD中的作用，并评价瘦素对棕榈酸（PA）诱导的肾小管上皮细胞（NRK-52E）的降脂作用。采用高脂饮食8周后单次腹腔注射链脲佐菌素（STZ, 30 mg/kg）建立SD大鼠DKD模型。然后观察脂质代谢相关标志物的表达变化。第12周，脂质沉积标志物脂肪分化相关蛋白（ADRP）表达水平显著升高。脂质合成标志物甾醇调节元件结合蛋白1c （SREBP 1c）高表达，而抑制SREBP 1c的关键分子胰岛素诱导基因1 （Insig-1）表达降低。将瘦素和化合物c与pa诱导的NRK-52E细胞孵育，研究其降脂作用，以及这种作用是否由AMPK/ insg -1/SREBP 1c信号通路介导。瘦素处理后，ADRP和SREBP 1c mRNA和蛋白含量降低，insg -1和磷酸化amp活化蛋白激酶（AMPK）升高。相反，在pa诱导的细胞中，化合物c对AMPK磷酸化的抑制大部分消除了瘦素的降脂作用。综上所述，这些结果提示DKD大鼠肾小管上皮细胞存在ELD。在pa诱导的NRK-52E细胞中，Leptin通过激活AMPK来减弱ELD，从而上调insg -1的表达水平。
Diabetic kidney disease (DKD) is a major health burden closely related to lipid metabolism disorders. Leptin has lipid-lowering efficacy, but the specific mechanism of its local effects on kidney is still unclear. This study aims to investigate the role of ectopic lipid deposition (ELD) in DKD and evaluate the lipid-lowering efficacy of leptin in the palmitic acid (PA)-induced renal tubular epithelial cells (NRK-52E). DKD model was established inSprague–Dawley(SD) rats by giving single intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) after high-fat diet for 8 weeks. Then, the expression changes of lipid metabolism-related markers were observed. At week 12, the protein expression level of lipid-deposited marker adipose differentiation-related protein (ADRP) was significantly increased. Besides, the lipid synthesis marker sterol regulatory element-binding protein 1c (SREBP 1c) was highly expressed while the expression of insulin-induced gene 1 (Insig-1), a key molecular of inhibiting SREBP 1c, was decreased. Leptin and compound c were incubated with the PA-induced NRK-52E cells to investigate the lipid-lowering effects and whether this effect was mediated by the AMPK/Insig-1/SREBP 1c signaling pathways. mRNA and protein of ADRP and SREBP 1c were reduced after leptin treatment, while Insig-1 and phosphorylated AMP-activated protein kinase (AMPK) were increased. Conversely, inhibition of AMPK phosphorylation by compound c mostly eliminated lipid-lowering efficacy of leptin in PA-induced cells. Collectively, these results suggested that there was ELD of renal tubular epithelial cells in DKD rats. Leptin upregulated the expression level of Insig-1 by activating AMPK to attenuate ELD in PA-induced NRK-52E cells.