Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA ; Department of Anesthesiology and Perioperative Medicine, Georgia Regents University , Augusta, GA , USA ; Vascular Biology Center, Georgia Regents University , Augusta, GA , USA.
Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA.
Front Immunol. 2013 Dec 24;4:480. doi: 10.3389/fimmu.2013.00480. eCollection 2013.
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.
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.
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.
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.
l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.
糖尿病肾病（DN）是终末期肾病的主要病因，与血管内皮功能障碍有关。慢性补充血管内皮一氧化氮合酶（eNOS）的底物 l-精氨酸（l-arg）未能改善血管功能。l-瓜氨酸（l-cit）补充不仅增加 l-arg 的合成，而且还抑制血管中的细胞质精氨酸酶 I，这是 eNOS 利用 l-arg 的竞争者。
研究 l-cit 治疗是否能降低链脲佐菌素（STZ）诱导的 1 型糖尿病（T1D）小鼠和大鼠的糖尿病肾病，并研究其对主要肾同工型精氨酸酶 II（ArgII）功能的影响。
STZ-C57BL6 小鼠接受 l-cit 或补充在饮用水中的载体。为了进行比较分析，评估了糖尿病 ArgII 敲除小鼠和 l-cit 治疗的 STZ 大鼠。
l-citrulline 在 STZ 大鼠的肾脏中发挥保护作用，并显著降低未经治疗的糖尿病小鼠中观察到的尿白蛋白排泄、肾小管间质纤维化和肾脏肥大。有趣的是，l-cit 治疗伴随着肾小管 ArgII 的持续升高，并且显著增加了抗炎细胞因子 IL-10 的血浆水平。糖尿病 ArgII 敲除小鼠的血尿素氮水平、肥大和扩张的肾小管比糖尿病野生型（WT）小鼠更高。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 动物没有明显差异。l-cit 还恢复了高糖处理的人肾小球内皮细胞单层中的一氧化氮/活性氧平衡和屏障功能。此外，l-cit 还具有建立抗炎表型的能力，其特征是在人近端肾小管细胞中增加 IL-10 和减少 IL-1β 和 IL-12(p70)的产生。
l-citrulline 补充建立了抗炎表型，并在 T1D 期间显著保留了肾单位的功能。
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