Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav-IPN), México D.F., 07360, Mexico.
Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), 04510 University City D.F., Mexico.
J Nutr Biochem. 2015 May;26(5):441-54. doi: 10.1016/j.jnutbio.2014.11.018. Epub 2015 Jan 29.
We previously reported that diabetes decreased the expression of renal tight junction (TJ) proteins claudin-5 in glomerulus, and claudin-2 and occludin in proximal tubule through an oxidative stress dependent way. Now we investigated whether all-trans retinoic acid (atRA), a compound that plays a relevant role in kidney maintenance and that possesses antioxidant properties, prevents loss of TJ proteins in streptozotocin (STZ)-treated rats. atRA was administered daily by gavage (1mg/kg) from Days 3-21 after STZ administration. atRA attenuated loss of body weight, proteinuria and natriuresis but it did not prevent hyperglucemia. Other metabolic alterations, such as: increased kidney injury molecule (KIM)-1, oxidative stress, protein kinase C (PKC) beta 2, NADPH oxidase subunits (p47(phox) and gp91(phox)) expressions and endothelial nitric oxide synthase (eNOS) uncoupling, and decreased nitric oxide synthesis, nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions were also attenuated by atRA. In vitro scavenging capacity assays showed that atRA scavenged peroxyl radicals (ROO•), singlet oxygen ((1)O2) and hypochlorous acid (HOCl) in a concentration-dependent manner. Decreased expressions of occludin, claudins-2 and -5 induced by diabetes were ameliorated by atRA. We also found that diabetes induced tyrosine nitration (3-NT), SUMOylation and phosphorylation in serine residues of claudin-2 and atRA prevented these changes. In conclusion, atRA exerted nephroprotective effects by attenuating oxidative stress and preventing loss of renal TJ proteins.
我们之前曾报道过，糖尿病通过氧化应激依赖性途径降低了肾小球中紧密连接（TJ）蛋白 Claudin-5 的表达，以及近端小管中 Claudin-2 和 Occludin 的表达。现在，我们研究了全反式视黄酸（atRA）是否可以预防链脲佐菌素（STZ）处理的大鼠 TJ 蛋白丢失。atRA 通过灌胃（1mg/kg）每天给药，从 STZ 给药后第 3 天至第 21 天给药。atRA 减轻了体重减轻、蛋白尿和排钠，但不能预防高血糖。其他代谢改变，如：增加肾脏损伤分子（KIM）-1、氧化应激、蛋白激酶 C（PKC）β2、NADPH 氧化酶亚基（p47（phox）和 gp91（phox））表达和内皮型一氧化氮合酶（eNOS）解偶联，以及减少一氧化氮合成、核因子-红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）表达，也被 atRA 减弱。体外清除能力测定表明，atRA 以浓度依赖的方式清除过氧自由基（ROO•）、单线态氧（（1）O2）和次氯酸（HOCl）。糖尿病引起的 Occludin、Claudin-2 和 Claudin-5 表达减少被 atRA 改善。我们还发现，糖尿病诱导 Claudin-2 中酪氨酸硝化（3-NT）、SUMO 化和丝氨酸残基磷酸化，而 atRA 可预防这些变化。总之，atRA 通过减轻氧化应激和防止肾脏 TJ 蛋白丢失发挥肾脏保护作用。
