São Paulo State University (Unesp), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil.
São Paulo State University (Unesp), Araraquara School of Dentistry, Department of Physiology and Pathology, Araraquara, São Paulo, Brazil.
Life Sci. 2020 Oct 1;258:118196. doi: 10.1016/j.lfs.2020.118196. Epub 2020 Aug 5.
The pharmacological properties of pentoxifylline have been re-evaluated, particularly in chronic kidney disease in diabetes, favored by its anti-inflammatory action. Definitive evidences of renal outcomes are lacking, which indicates the need for investigation of novel mechanisms of action of pentoxifylline. We postulated that components associated with the metabolism of advanced glycation end products (AGEs) may be modulated by pentoxifylline, which consequently decreases the detrimental effects of obesity on kidneys.
C57BL-6J mice were fed a high-fat diet for 14 weeks and treated with 50 mg/kg pentoxifylline during the last 7 weeks. Changes in the renal levels of AGE metabolism-associated components were investigated, with particular focus on the receptor for AGEs (RAGE), its downstream components, and components related to AGE detoxification, including glyoxalase 1 (GLO 1).
Pentoxifylline reduced body weight gain, improved insulin sensitivity and glucose tolerance, downregulated biomarkers of glycoxidative stress, and enhanced plasma paraoxonase 1 activity. In the kidneys, pentoxifylline inhibited glomerular expansion, lipid deposition, reduced pro-inflammatory cytokine levels, and induced the activation of AMP-activated protein kinase. Pentoxifylline inhibited the renal accumulation of AGEs and reduced the levels of RAGE and its downstream components, and consequently mitigated oxidative stress and apoptosis. Pentoxifylline also increased the renal levels of GLO 1 and the activities of antioxidant enzymes. Urinary albumin levels were observed to be lowered, which reconfirmed the antialbuminuric effects of pentoxifylline.
The novel mechanisms of action help explain the renoprotective effects of pentoxifylline and the attenuation of obesity-associated renal complications related to glycoxidative stress.
已重新评估了己酮可可碱的药理学特性，特别是在糖尿病慢性肾脏病中，这得益于其抗炎作用。缺乏有关肾脏结局的明确证据，这表明需要研究己酮可可碱的新作用机制。我们推测，与晚期糖基化终产物（AGE）代谢相关的成分可能会被己酮可可碱调节，从而减轻肥胖对肾脏的有害影响。
C57BL-6J 小鼠喂食高脂肪饮食 14 周，并在最后 7 周用 50mg/kg 己酮可可碱治疗。研究了肾脏 AGE 代谢相关成分的变化，特别关注 AGE 受体（RAGE）及其下游成分，以及与 AGE 解毒有关的成分，包括甘油醛 3-磷酸脱氢酶（GLO1）。
己酮可可碱可减轻体重增加，改善胰岛素敏感性和葡萄糖耐量，下调糖基化应激生物标志物，并增强血浆对氧磷酶 1 活性。在肾脏中，己酮可可碱抑制肾小球扩张，减少脂质沉积，降低促炎细胞因子水平，并诱导 AMP 激活蛋白激酶的激活。己酮可可碱抑制肾脏 AGE 的积累，降低 RAGE 及其下游成分的水平，从而减轻氧化应激和细胞凋亡。己酮可可碱还增加了肾脏 GLO1 的水平和抗氧化酶的活性。观察到尿白蛋白水平降低，这再次证实了己酮可可碱的抗白蛋白尿作用。
新的作用机制有助于解释己酮可可碱的肾脏保护作用，并减轻与糖基化应激相关的肥胖相关肾脏并发症。
