Dapagliflozin Treatment Augments Bioactive Phosphatidylethanolamine Concentrations in Kidney Cortex Membrane Fractions of Hypertensive Diabetic db/db Mice and Alters the Density of Lipid Rafts in Mouse Proximal Tubule Cells.
Dapagliflozin Treatment Augments Bioactive Phosphatidylethanolamine Concentrations in Kidney Cortex Membrane Fractions of Hypertensive Diabetic db/db Mice and Alters the Density of Lipid Rafts in Mouse Proximal Tubule Cells.
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DOI：
10.3390/ijms24021408
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发表时间：
2023-01-11
影响因子：
5.6
通讯作者：
Alli, Abdel A.
中科院分区：
文献类型：
--
作者：
Gholam, Mohammed F.;Liu, Lauren P.;Searcy, Louis A.;Denslow, Nancy D.;Alli, Abdel A.
除了抑制肾脏葡萄糖重吸收和允许葡萄糖排泄外，钠/葡萄糖协同转运蛋白2（SGLT 2）抑制剂达格列净可能有效治疗与2型糖尿病（T2DM）相关的各种合并症。达格列净发挥其有益作用的分子机制在很大程度上是未知的。我们假设糖尿病肾脏中的达格列净治疗改变了质膜脂质组成，抑制了肾细胞的细胞外囊泡（EV）释放，并破坏了近端小管细胞中的脂筏。为了检验这一假设，我们用达格列净（N = 8）或溶剂（N = 8）处理糖尿病db/db小鼠，并进行基于质谱的脂质组学研究肾皮质中膜脂质浓度的变化。此外，我们从小鼠活动期和非活动期收集的尿样中分离出尿EV（uEV），然后探索EV中富集的膜蛋白的变化。多种三酰甘油（TAG）富集在溶剂处理的糖尿病db/db小鼠的肾皮质膜组分中，而多种磷脂酰乙醇胺的水平在用达格列净处理的类似小鼠中显著更高。在达格列净治疗的糖尿病小鼠的非活动期收集的尿样中EV浓度和大小较小。在用达格列净处理的培养的小鼠近端小管细胞中，脂筏蛋白小窝蛋白-1从密度较低的部分转移到密度较高的蔗糖密度梯度部分。总之，这些结果表明达格列净可能调节糖尿病肾脏中脂质介导的信号转导。
In addition to inhibiting renal glucose reabsorption and allowing for glucose excretion, the sodium/glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin may be efficacious in treating various comorbidities associated with type 2 diabetes mellitus (T2DM). The molecular mechanisms by which dapagliflozin exerts its beneficial effects are largely unknown. We hypothesized dapagliflozin treatment in the diabetic kidney alters plasma membrane lipid composition, suppresses extracellular vesicle (EV) release from kidney cells, and disrupts lipid rafts in proximal tubule cells. In order to test this hypothesis, we treated diabetic db/db mice with dapagliflozin (N = 8) or vehicle (N = 8) and performed mass spectrometry-based lipidomics to investigate changes in the concentrations of membrane lipids in the kidney cortex. In addition, we isolated urinary EVs (uEVs) from urine samples collected during the active phase and the inactive phase of the mice and then probed for changes in membrane proteins enriched in the EVs. Multiple triacylglycerols (TAGs) were enriched in the kidney cortex membrane fractions of vehicle-treated diabetic db/db mice, while the levels of multiple phosphatidylethanolamines were significantly higher in similar mice treated with dapagliflozin. EV concentration and size were lesser in the urine samples collected during the inactive phase of dapagliflozin-treated diabetic mice. In cultured mouse proximal tubule cells treated with dapagliflozin, the lipid raft protein caveolin-1 shifted from less dense fractions to more dense sucrose density gradient fractions. Taken together, these results suggest dapagliflozin may regulate lipid-mediated signal transduction in the diabetic kidney.
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影响因子：
5.5
作者：
Chacko KM;Nouri MZ;Schramm WC;Malik Z;Liu LP;Denslow ND;Alli AA
通讯作者：
Alli AA
影响因子：
39.3
作者：
Paneni F;Beckman JA;Creager MA;Cosentino F
通讯作者：
Cosentino F
影响因子：
5.3
作者：
Al-Sharea A;Murphy AJ;Huggins LA;Hu Y;Goldberg IJ;Nagareddy PR
通讯作者：
Nagareddy PR
DOI：
10.1007/s11306-021-01816-0
发表时间：
2021-07-04
期刊：
Metabolomics : Official journal of the Metabolomic Society
影响因子：
--
作者：
Sas KM;Lin J;Wang CH;Zhang H;Saha J;Rajendiran TM;Soni T;Nair V;Eichinger F;Kretzler M;Brosius FC 3rd;Michailidis G;Pennathur S
通讯作者：
Pennathur S
影响因子：
3.7
作者：
Jella KK;Yu L;Yue Q;Friedman D;Duke BJ;Alli AA
通讯作者：
Alli AA