Univ. of Utah and Veteran Affairs Medical Center, Division of Nephrology and Hypertension, 30 N 1900 E, Rm. 4R312, Salt Lake City, UT 84132.
Am J Physiol Renal Physiol. 2013 Dec 1;305(11):F1555-62. doi: 10.1152/ajprenal.00157.2013. Epub 2013 Aug 14.
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). The inhibitors of renin-angiotensin-aldosterone system (RAAS) can alleviate some of the symptoms of DN but fail to stop the progression to ESRD. Our previous studies demonstrate renoprotective action of nitro-oleic acid (OA-NO2) in several rodent models of renal disease. Here we examined the therapeutic potential and the underlying mechanism of combination of losartan and OA-NO2 in db/db mice. OA-NO2 was infused at 5 mg·kg(-1)·day(-1) via osmotic minipump, and losartan was incorporated into diet at 10 mg·kg(-1)·day(-1), each administered alone or in combination for 2 wk. Diabetic db/db mice developed progressive albuminuria and glomerulosclerosis, accompanied by podocytes loss, increased indexes of renal fibrosis, oxidative stress, and inflammation. Treatment of the diabetic mice with OA-NO2 or losartan alone moderately ameliorated kidney injury; however, the combined treatment remarkably reduced albuminuria, restored glomerular filtration barrier structure, and attenuated glomerulosclerosis, accompanied with significant suppression of renal oxidative stress and inflammation. These data demonstrate that combination of losartan and OA-NO2 effectively reverses renal injury in DN.
糖尿病肾病（DN）是终末期肾病（ESRD）的主要原因。肾素-血管紧张素-醛固酮系统（RAAS）抑制剂可以缓解 DN 的一些症状，但无法阻止其向 ESRD 进展。我们之前的研究表明，硝基油酸（OA-NO2）在几种肾脏疾病的啮齿动物模型中具有肾保护作用。在这里，我们研究了洛沙坦和 OA-NO2 联合治疗 db/db 小鼠的治疗潜力及其潜在机制。通过渗透微型泵以 5mg·kg(-1)·day(-1)的剂量输注 OA-NO2，将洛沙坦掺入饮食中，剂量为 10mg·kg(-1)·day(-1)，单独或联合给药 2 周。糖尿病 db/db 小鼠逐渐出现白蛋白尿和肾小球硬化，伴有足细胞丢失、肾纤维化、氧化应激和炎症指标增加。单独用 OA-NO2 或洛沙坦治疗糖尿病小鼠可适度改善肾脏损伤；然而，联合治疗可显著减少白蛋白尿，恢复肾小球滤过屏障结构，并减轻肾小球硬化，同时显著抑制肾脏氧化应激和炎症。这些数据表明，洛沙坦和 OA-NO2 的联合治疗可有效逆转 DN 中的肾脏损伤。
