Novoa Ulises, Soto Karen, Valdés Cristian, Villaseñor Jorge, Treuer Adriana V, González Daniel R
Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Avenida Lircay s/n, Talca 3460000, Chile.
Centro de Investigación de Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca 3466706, Chile.
Biomedicines. 2022 Oct 4;10(10):2479. doi: 10.3390/biomedicines10102479.
Background: The effects of diabetes on the cardiovascular system as well as in the kidney are profound, which include hypertrophy and fibrosis. Diabetes also induces oxidative stress, at least in part due to the uncoupling of nitric oxide synthase (NOS); this is a shift in NO production toward superoxide production due to reduced levels of the NOS cofactor tetrahydrobiopterin (BH4). With this in mind, we tested the hypothesis that BH4 supplementation may prevent the development of diabetic cardiomyopathy and nephropathy. Methods: Diabetes was induced in Balb/c mice with streptozotocin. Then, diabetic mice were divided into two groups: one group provided with BH4 (sapropterin) in drinking water (daily doses of 15 mg/kg/day, during eight weeks) and the other that received only water. A third group of normoglycemic mice that received only water were used as the control. Results: Cardiac levels of BH4 were increased in mice treated with BH4 (p = 0.0019). Diabetes induced cardiac hypertrophy, which was prevented in the group that received BH4 (p < 0.05). In addition, hypertrophy was evaluated as cardiomyocyte cross-sectional area. This was reduced in diabetic mice that received BH4 (p = 0.0012). Diabetes induced cardiac interstitial fibrosis that was reduced in mice that received BH4 treatment (p < 0.05). We also evaluated in the kidney the impact of BH4 treatment on glomerular morphology. Diabetes induced glomerular hypertrophy compared with normoglycemic mice and was prevented by BH4 treatment. In addition, diabetic mice presented glomerular fibrosis, which was prevented in mice that received BH4. Conclusions: These results suggest that chronic treatment with BH4 in mice ameliorates the cardiorenal effects of diabetes,, probably by restoring the nitroso−redox balance. This offers a possible new alternative to explore a BH4-based treatment for the organ damage caused by diabetes.
糖尿病对心血管系统以及肾脏的影响是深远的，包括肥大和纤维化。糖尿病还会诱导氧化应激，至少部分原因是一氧化氮合酶（NOS）解偶联；这是由于NOS辅因子四氢生物蝶呤（BH4）水平降低，导致NO生成向超氧化物生成转变。考虑到这一点，我们检验了补充BH4可能预防糖尿病性心肌病和肾病发展的假设。方法：用链脲佐菌素诱导Balb/c小鼠患糖尿病。然后，将糖尿病小鼠分为两组：一组在饮用水中给予BH4（司来吉兰，每日剂量15毫克/千克/天，持续八周），另一组只给予水。第三组正常血糖小鼠只给予水作为对照。结果：接受BH4治疗的小鼠心脏中BH4水平升高（p = 0.0019）。糖尿病诱导心脏肥大，而接受BH4的组中这种情况得到预防（p < 0.05）。此外，肥大通过心肌细胞横截面积进行评估。接受BH4的糖尿病小鼠中这一指标降低（p = 0.0012）。糖尿病诱导心脏间质纤维化，接受BH4治疗的小鼠中这种情况减轻（p < 0.05）。我们还在肾脏中评估了BH4治疗对肾小球形态的影响。与正常血糖小鼠相比，糖尿病诱导肾小球肥大，而BH4治疗可预防这种情况。此外，糖尿病小鼠出现肾小球纤维化，接受BH4的小鼠中这种情况得到预防。结论：这些结果表明，小鼠长期接受BH4治疗可改善糖尿病的心脏和肾脏影响，可能是通过恢复亚硝基 - 氧化还原平衡。这为探索基于BH4的治疗方法来治疗糖尿病引起的器官损伤提供了一种可能的新选择。
