Diabetic nephropathy (DN) remains the most common cause of end-stage renal disease. Although, adenosine acts as a local modulator with a cytoprotective function, extracellular adenosine usually disappears quickly due to a rapid uptake into adjacent cells. Therefore, we investigated the effect of 5'-(N-ethylcarboxamido)-adenosine (NECA), a stable, nonselective adenosine receptor agonist, on diabetes-induced increases in inflammatory cytokines and adhesion molecules. The enhancement of adenosine receptor action by NECA was examined in the renal tissues of rats with streptozotocin-induced diabetes. Daily i.p. injections of NECA at 0.3 mg/kg/day were given to rats, over a two-week period, six weeks after the induction of diabetes. Morphological changes were assessed in kidney sections. Oxidative stress was examined by measuring tissue malondialdehyde. Gene expression of interleukin (IL)-18, tumor necrosis factor (TNF)-α and intercellular adhesion molecule (ICAM)-1 was measured by real-time PCR. Activation of cellular, proapoptotic pathways was demonstrated by measuring the activation of c-Jun NH(2)-terminal kinases (JNK)-mitogen-activated-protein kinase (MAPK). We found that diabetes-induced malondialdehyde formation activated the production of IL-18, TNF-α and ICAM-1, which, in turn, activated pro-apoptotic pathways in diabetic rats. Treatment with NECA protected diabetic rats by exerting hypoglycemic and antioxidant effects as well as reducing gene expression of proinflammatory cytokines. These effects were associated with deactivation of JNK-MAPK. In addition, diabetic rats treated with NECA showed mild glomerular effects and vacuolation of tubular epithelium. We can conclude that activation of adenosine receptors is a potential therapeutic target in DN. NECA acts via multiple mechanisms including: reducing diabetes-induced oxidative stress, inhibiting gene expression of IL-18, TNF-α and ICAM-1, and blocking activation of the JNK-MAPK pathway.

中文翻译：

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NECA在糖尿病肾病中的肾脏保护作用：IL-18和ICAM-1的意义。

糖尿病肾病（DN）仍然是终末期肾脏疾病的最常见原因。尽管腺苷充当具有细胞保护功能的局部调节剂，但由于迅速吸收邻近细胞，细胞外腺苷通常迅速消失。因此，我们研究了5'-（N-乙基羧酰胺基）-腺苷（NECA）（一种稳定的非选择性腺苷受体激动剂）对糖尿病引起的炎性细胞因子和粘附分子增加的影响。在链脲佐菌素诱发的糖尿病大鼠的肾组织中检查了NECA对腺苷受体作用的增强作用。在糖尿病诱导后六周的两周内，每天以0.3 mg / kg /天的腹腔注射NECA给予大鼠。评估肾脏切片的形态变化。通过测量组织丙二醛来检查氧化应激。通过实时PCR检测白介素（IL）-18，肿瘤坏死因子（TNF）-α和细胞间粘附分子（ICAM）-1的基因表达。通过测量c-Jun NH（2）末端激酶（JNK）-丝裂原活化的蛋白激酶（MAPK）的激活，证明了细胞凋亡途径的激活。我们发现，糖尿病诱导的丙二醛形成激活了IL-18，TNF-α和ICAM-1的产生，进而激活了糖尿病大鼠的促凋亡途径。NECA的治疗通过发挥降糖和抗氧化作用以及减少促炎细胞因子的基因表达来保护糖尿病大鼠。这些作用与JNK-MAPK失活有关。此外，用NECA治疗的糖尿病大鼠显示出轻度的肾小球作用和肾小管上皮的空泡化。我们可以得出结论，腺苷受体的激活是DN中潜在的治疗靶点。NECA通过多种机制起作用，包括：降低糖尿病引起的氧化应激，抑制IL-18，TNF-α和ICAM-1的基因表达，以及阻断JNK-MAPK途径的激活。