Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes.
Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes.
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DOI：
10.1007/s00125-017-4469-y
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发表时间：
2018-03
期刊：
影响因子：
8.2
通讯作者：
Solito E
中科院分区：
文献类型：
--
作者：
Purvis GSD;Chiazza F;Chen J;Azevedo-Loiola R;Martin L;Kusters DHM;Reutelingsperger C;Fountoulakis N;Gnudi L;Yaqoob MM;Collino M;Thiemermann C;Solito E
心脏和肾脏的微血管并发症与炎症的总体上升密切相关。膜联蛋白A1 （ANXA1）是一种内源性抗炎分子，可以限制和解决炎症。在这项研究中，我们采用了床边到实验室的方法来研究：(1)1型糖尿病患者的ANXA1水平；(2)内源性ANXA1在实验性1型糖尿病肾病和心肌病中的作用；(3)人重组ANXA1治疗能否减轻1型糖尿病小鼠模型的肾病和心肌病。测定伴有或不伴有肾病的1型糖尿病患者和健康供者血浆中的ANXA1。C57BL/6或Anxa1 - / -小鼠注射链脲佐菌素（STZ； 45 mg/kg每天静脉注射，连续5天）诱导小鼠实验性1型糖尿病。用人重组（hr）ANXA1 （1 μl, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4，灌胃）或对照（100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4，灌胃）处理糖尿病小鼠。伴有/不伴有肾病的1型糖尿病患者血浆ANXA1水平高于健康人群（66.0±4.2/64.0±4 ng/ml vs 35.9±2.3 ng/ml; p < 0.05）。与糖尿病野生型（WT）小鼠相比，糖尿病Anxa1−/−小鼠表现出更差的糖尿病表型，并发生更严重的心脏（射血分数；76.1±1.6% vs 49.9±0.9%）和肾功能障碍（蛋白尿；89.3±5.0 μg/mg vs 113.3±5.5 μg/mg）。机制上，与非糖尿病WT小鼠相比，非糖尿病Anxa1−/−小鼠心脏和肾脏中丝裂原活化蛋白激酶（MAPKs） p38、c-Jun n末端激酶（JNK）和细胞外信号调节激酶（ERK）的磷酸化程度均显著升高，并且在stz诱导的1型糖尿病后进一步增强。hrANXA1预防性治疗（第1-13周）可减轻与stz诱导的糖尿病相关的心脏（射血分数：54.0±1.6% vs 72.4±1.0%）和肾脏（蛋白尿：89.3±5.0 μg/mg vs 53.1±3.4 μg/mg）功能障碍，而hrANXA1治疗性治疗（第8-13周）在已经出现明显的心脏和肾脏功能障碍后，可阻止糖尿病小鼠心脏和肾脏功能的进一步下降。此外，给药hrANXA1可减弱糖尿病小鼠p38、JNK和ERK磷酸化的增加，并恢复Akt的磷酸化。总之，这些结果表明，1型糖尿病患者血浆中ANXA1水平升高与肾功能的显著损害无关。此外，在stz诱导的1型糖尿病小鼠模型中，ANXA1通过将MAPK信号恢复到基线并激活促生存通路（Akt）来保护心脏和肾脏功能障碍。我们建议ANXA1是控制1型糖尿病合并症的潜在治疗选择。本文的在线版本（10.1007/s00125-017-4469-y）包含同行评审但未经编辑的补充材料，授权用户可使用。
Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 −/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1 (1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.). Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1 −/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with non-diabetic WT mice, the degree of the phosphorylation of mitogen-activated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1 −/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1–13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8–13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. Overall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with type 1 diabetes independent of a significant impairment in renal function. Furthermore, in mouse models with STZ-induced type 1 diabetes, ANXA1 protects against cardiac and renal dysfunction by returning MAPK signalling to baseline and activating pro-survival pathways (Akt). We propose ANXA1 to be a potential therapeutic option for the control of comorbidities in type 1 diabetes. The online version of this article (10.1007/s00125-017-4469-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
5.4
作者：
Johnson FL;Patel NSA;Purvis GSD;Chiazza F;Chen J;Sordi R;Hache G;Merezhko VV;Collino M;Yaqoob MM;Thiemermann C
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