Therapeutic strategies of redox modification for renal failure

肾功能衰竭是一种综合征，其特征是突然的，在大多数情况下，可逆的肾功能障碍，或进行性的，在大多数情况下，不可逆的肾功能障碍。刺激因素的范围很广，肾衰竭的病理生理包括内皮、肾小球和肾小管功能障碍，其严重程度和出现时间各不相同。本项目旨在研究氧化应激和亚硝化应激对体内和体外肾损伤的贡献。本项目的结果如下：(1)我们通过大鼠急性肾功能衰竭模型证明，L-Nil（诱导型NO合成酶抑制剂）、卵磷脂化SOD和ebselen（过氧亚硝酸盐清道夫）治疗通过抑制过氧亚硝酸盐的产生或清除来改善肾功能，从而防止脂质过氧化和氧化性DNA损伤。(2)我们发现亚甲基四氢drofolate还原酶（MTHFR） TT基因型可能与儿童节段性肾小球硬化的早期发生和进展有关。(3)我们研究了晚期糖基化终产物（AGE）的产生和氧化应激是否在1型糖尿病早期临床阶段的年轻患者中增加。结果表明，AGEs的积累（其形成与氧化应激密切相关）和由此导致的内皮功能障碍可能在1型糖尿病的早期就开始了。(4)采用ECIS技术检测NO对人微血管内皮细胞粘附的影响。结果表明，NO可调节内皮细胞的细胞-基质和/或细胞-细胞粘附，并可能改变人体组织和器官的微血管通透性。(5)综述了NO氧化和歧化的基本化学性质，建立了在任意NO（含O_2）和任何时间生成NO_2或N_2O的可靠预测公式。少

Renal failure is a syndrome characterized by an abrupt, in most cases, reversible kidney dysfunction, or a progressive, in most cases, irreversible kidney dysfunction. The spectrum of inciting factors is broad, and the pathophysiology of renal failure includes endothelial, glomerular and tubular dysfunction, which vary in severity and time of appearance. The present project was designed to examine the contribution of oxidative and nitrosative stress to the renal damage in vivo and in vitro situations. The results obtained with this project are the following.(1) We have demonstrated using the rat model of acute renal failure that L-Nil (inducible NO synthase inhibitor), lecithinized SOD, and ebselen (scavenger of peroxynitrite) treatments improve renal function due to their suppression of peroxynitrite production or its scavenging, consequently preventing lipid peroxidation and oxidative DNA damage.(2) We have found that the methylenetetrahy drofolate reductase (MTHFR) TT genotype may b … More e associated with early development and progression of childhood segmental glomerulosclerosis.(3) We examined whether advanced glycosylation end product (AGE) production and oxidative stress are augmented in young patients with type 1 diabetes at early clinical stages of the disease. The results have indicated that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type 1 diabetes.(4) We examined the effect of NO on the adhesion of human microvascular endothelial cells using the ECIS technique. The results have suggested that NO modulates cell-matrix and/or cell-cell adhesion in endothelial cells and that this molecule might modify microvascular permeability in human tissues and organs.(5) We have reviewed basic chemical aspects of the oxidation and disproportionation of NO, and also established the formulas for reliably predicting NO_2 or N_2O formation in any set of NO (with O_2) and in any time. Less