Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1
Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1
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DOI：
10.1016/j.biopha.2023.115840
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发表时间：
2023-11-06
影响因子：
7.5
通讯作者：
Zha，Yan
中科院分区：
文献类型：
--
作者：
Da，Jingjing;Xu，Yongjie;Zha，Yan
背景：下丘脑神经炎症与脂质代谢紊乱有关。考虑到钠-葡萄糖共转运蛋白2（SGLT2）抑制剂的抗神经炎症作用，假设中央给药达格列净可提供下丘脑保护并改变肾脏脂质代谢，以预防糖尿病肾病（DKD）。方法采集DKD患者血液标本。采用30 mg/kg链脲佐菌素和高脂饮食、db/dbmice和棕榈酸刺激BV2小胶质细胞的SD雄性大鼠作为研究模型。侧脑室注射达格列净0.28 mg/3ul；采用qPCR、western blotting、免疫荧光和免疫组织化学染色检测基因和蛋白表达水平。ELISA法测定血清IL-1β和IL-6的含量。采用油红O染色、脂质组学和非靶向代谢组学评价肾脏脂质代谢异常。结果血清MCPIP1降低是DKD患者肾脏进展的独立危险因素（OR=1.22, 95% CI: 1.02 ~ 1.45，P= 0.033）。DKD大鼠下丘脑小胶质细胞标志物IBA1升高，MCPIP1降低，肾脏脂滴沉积增加。中枢达格列净能降低血糖、降低下丘脑炎性细胞因子、降低肾小管脂滴沉积。脂质组学和代谢组学结果显示，达格列净改变了37种脂质和19种被认为促进脂肪分解的代谢物。这些脂质代谢变化归因于达格列净通过上调MCPIP1，抑制PA诱导的小胶质细胞中的细胞因子。结论中央给药达格列净通过上调小胶质细胞MCPIP1水平和改变DKD肾脏脂质代谢而发挥抗炎作用。
BackgroundHypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD).MethodsBlood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet,db/dbmice and palmitic acid (PA)-stimulated BV2 microglia were used for study models. 0.28 mg/3ul dapagliflozin was injected into the lateral ventricle indb/dbmice. Genes and protein expression levels were determined by qPCR, western blotting, immunofluorescence, and immunohistochemistry staining. Secreted IL-1β and IL-6 were quantified by ELISA. Oil red O staining, lipidomic, and non-targeted metabolomics were performed to evaluate abnormal lipid metabolism in kidney.ResultsThe decrease of serum MCPIP1 was an independent risk factor for renal progression in DKD patients (OR=1.22,95 %CI: 1.02–1.45,P= 0.033). Higher microglia marker IBA1 and lower MCPIP1 in the hypothalamus, as well as lipid droplet deposition increasing in the kidney were observed in DKD rats. Central dapagliflozin could reduce the blood sugar, hypothalamic inflammatory cytokines, lipid droplet deposition in renal tubular. Lipidomics and metabolomics results showed that dapagliflozin changed 37 lipids and 19 metabolites considered on promoting lipolysis. These lipid metabolism changes were attributed to dapagliflozin by upregulating MCPIP1, and inhibiting cytokines in the microglia induced by PA.ConclusionsCentral administrated Dapagliflozin elicits an anti-inflammatory effect by upregulating MCPIP1 levels in microglia and changes lipid metabolism in kidney of DKD.