l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice.
l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice.
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DOI：
10.3389/fimmu.2013.00480
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发表时间：
2013
影响因子：
7.3
通讯作者：
Caldwell RW
中科院分区：
文献类型：
--
作者：
Romero MJ;Yao L;Sridhar S;Bhatta A;Dou H;Ramesh G;Brands MW;Pollock DM;Caldwell RB;Cederbaum SD;Head CA;Bagi Z;Lucas R;Caldwell RW
理由：糖尿病肾病（DN）是终末期肾脏疾病的主要原因，与内皮功能障碍相关。长期补充l-精氨酸（l-arg），内皮一氧化氮合酶（eNOS）的底物，不能改善血管功能。补充l-瓜氨酸（l- citit）不仅可以增加l-精氨酸的合成，还可以抑制细胞内精氨酸酶I，这是eNOS在血管中使用l-精氨酸的竞争对手。目的：探讨l- citit治疗是否能降低链脲佐菌素（STZ）诱导的小鼠和大鼠1型糖尿病（T1D）的DN，并研究其对肾脏主要亚型精氨酸酶II （ArgII）功能的影响。方法：STZ-C57BL6小鼠分别在饮水中添加l-cit或载药。为了进行比较分析，我们对糖尿病ArgII敲除小鼠和l- citl处理的stz大鼠进行了评估。结果：l-瓜氨酸对stz大鼠肾脏有保护作用，在未经治疗的糖尿病小鼠中，可显著减少尿白蛋白排泄、小管间质纤维化和肾脏肥大。有趣的是，l-cit治疗在16周时伴有管状ArgII持续升高，并显著提高血浆抗炎细胞因子IL-10水平。糖尿病ArgII敲除小鼠比糖尿病野生型（WT）小鼠表现出更高的血尿素氮水平、肥大和扩张的小管。尽管ArgII敲除小鼠的胶原沉积明显减少，但它们的蛋白尿与糖尿病WT动物没有显著差异。l-Cit还能恢复高糖处理的人肾小球内皮细胞单层中一氧化氮/活性氧的平衡和屏障功能。此外，l- citit还具有抗炎作用，其特征是在人近端小管细胞中增加IL-10，减少IL-1β和IL-12（p70）的产生。结论：补充l-瓜氨酸具有抗炎作用，可显著保护大鼠T1D期间肾细胞功能。
Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of l-arginine (l-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. l-Citrulline (l-cit) supplementation not only increases l-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of l-arg, in the vasculature. Aims: To investigate whether l-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received l-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and l-cit-treated STZ-rats were evaluated. Results: l-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, l-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. l-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, l-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. Conclusion: l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.