The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease
The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease
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DOI：
10.1681/asn.2018030323
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发表时间：
2018-10-01
影响因子：
13.6
通讯作者：
Giani, Jorge F.
中科院分区：
文献类型：
--
作者：
Eriguchi, Masahiro;Bernstein, Ellen A.;Giani, Jorge F.
背景最近的证据强调了炎症在糖尿病肾病发展中的关键作用。血管紧张素转换酶（ACE）在调节糖尿病相关肾脏炎症反应中起积极作用。研究还表明，ACE在炎症和免疫反应中的作用不依赖于血管紧张素II。ACE的两个催化独立的结构域，N-和C-结构域，可以处理除了血管紧张素I以外的多种底物。方法为了检查每个ACE结构域对钠潴留状态、肾脏炎症和与糖尿病肾病相关的肾损伤的相对贡献，我们使用链脲佐菌素在野生型小鼠和缺乏功能性ACE N结构域的遗传小鼠模型中诱导糖尿病，结果与糖尿病野生型或CKO小鼠相比，糖尿病NKO小鼠对盐水攻击的反应是多排出32%的尿钠。与糖尿病野生型小鼠相比，糖尿病NKO小鼠的肾上皮钠通道裂解（通道活性的标志物）减少55%，肾IL-1 β减少55%，肾TNF-α减少53%，白蛋白尿减少53%。这种保护性表型与肾脏血管紧张素II水平的变化无关。此外，我们提出的证据表明，抗炎四肽N-乙酰-丝氨酰-乙酰-赖氨酰-脯氨酸（AcSDKP），ACE N-域特异性底物，在尿中积累的NKO小鼠，介导的有益效果观察NKO.Conclusions这些数据表明，增加AcSDKP通过阻断ACE N-域促进钠排泄和改善糖尿病肾病独立的肾内血管紧张素II调节。
Background Recent evidence emphasizes the critical role of inflammation in the development of diabetic nephropathy. Angiotensin-converting enzyme (ACE) plays an active role in regulating the renal inflammatory response associated with diabetes. Studies have also shown that ACE has roles in inflammation and the immune response that are independent of angiotensin II. ACE's two catalytically independent domains, the N- and C-domains, can process a variety of substrates other than angiotensin I.Methods To examine the relative contributions of each ACE domain to the sodium retentive state, renal inflammation, and renal injury associated with diabetic kidney disease, we used streptozotocin to induce diabetes in wild-type mice and in genetic mouse models lacking either a functional ACE N-domain (NKO mice) or C-domain (CKO mice).Results In response to a saline challenge, diabetic NKO mice excreted 32% more urinary sodium compared with diabetic wild-type or CKO mice. Diabetic NKO mice also exhibited 55% less renal epithelial sodium channel cleavage (a marker of channel activity), 55% less renal IL-1 beta, 53% less renal TNF-alpha, and 53% less albuminuria than diabetic wild-type mice. This protective phenotype was not associated with changes in renal angiotensin II levels. Further, we present evidence that the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain-specific substrate that accumulates in the urine of NKO mice, mediates the beneficial effects observed in the NKO.Conclusions These data indicate that increasing AcSDKP by blocking the ACE N-domain facilitates sodium excretion and ameliorates diabetic kidney disease independent of intrarenal angiotensin II regulation.