Renin-angiotensin system inhibition reverses the altered triacylglycerol metabolic network in diabetic kidney disease.
Renin-angiotensin system inhibition reverses the altered triacylglycerol metabolic network in diabetic kidney disease.
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DOI：
10.1007/s11306-021-01816-0
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发表时间：
2021-07-04
期刊：
影响因子：
--
通讯作者：
Pennathur S
中科院分区：
文献类型：
--
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
血脂异常是糖尿病肾病（DKD）进展的重要危险因素。确定不同 DKD 严重程度范围内个体脂质和脂质网络的变化，可以识别对 DKD 进展致病的脂质。我们对糖尿病 db/db 和 db/db eNOS−/− 小鼠以及非糖尿病同窝对照小鼠的肾皮质组织进行了非靶向脂质组学分析。一部分小鼠接受了肾素-血管紧张素系统 (RAS) 抑制剂赖诺普利和氯沙坦治疗，这改善了 db/db eNOS−/− 小鼠模型中的 DKD 表型。在本研究的三个自变量中，糖尿病对肾皮质总体脂质水平的影响最大，而 eNOS 表达和 RAS 抑制对肾脏脂质水平的影响较小。与 db/db 小鼠相比，db/db eNOS−/− 小鼠的肾脏脂质网络结构，特别是涉及甘油脂（如三酰甘油）的网络，因肾脏疾病恶化而受到严重破坏，这一特征可通过 RAS 抑制来逆转。这与硬脂酰辅酶 A 去饱和酶 Scd1 和 Scd2 的表达减少以及 RAS 抑制有关。除了已知的 RAS 抑制对 DKD 进展的有益作用外，我们的结果表明 RAS 抑制对肾脏三酰甘油脂质代谢网络的作用以前未被认识到。
Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). Determining the changes in individual lipids and lipid networks across a spectrum of DKD severity may identify lipids that are pathogenic to DKD progression. We performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS−/− mice along with non-diabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS−/− mouse model. Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS−/− mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network.
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