Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Geriatric Research Education and Clinical Center, South Texas Veterans Healthcare System and Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
J Diabetes Complications. 2019 Jan;33(1):23-32. doi: 10.1016/j.jdiacomp.2018.10.003. Epub 2018 Oct 13.
Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions and that overexpression of eNOS may protect against tissue injury. Our study revealed for the first time overexpression of eNOS leads to disease progression rather than protection. Transgenic mice selectively expressing eNOS in endothelial cells (eNOSTg) were cross bred with Ins2Akita type-1 (AK) diabetic mice to generate eNOS overexpressing eNOSTg/AK mice. Wild type, eNOSTg, AK and eNOSTg/AK mice were assessed for kidney function and blood glucose levels. Remarkably, overexpressing eNOSTg mice showed evidence of unpredicted glomerular injury with segmental mesangiolysis and occasional microaneurysms. Notably, in eNOSTg/AK mice overexpression of eNOS led to increased glomerular/endothelial injury that was associated with increased superoxide levels and renal dysfunction. Results indicate for the first time that overexpressing eNOS in endothelial cells cannot ameliorate diabetic lesions, but paradoxically leads to progression of nephropathy likely due to eNOS uncoupling and superoxide upsurge. This novel finding has a significant impact on current therapeutic strategies to improve endothelial function and prevent progression of diabetic renal disease. Further, the eNOSTg/AK model developed in this study has significant translational potentials for elucidating the underlying mechanism implicated in the deflected function of eNOS in diabetic nephropathy.
先前的研究表明，糖尿病小鼠中 eNOS 的全球缺乏会加剧肾脏损伤，而过表达 eNOS 可能有助于保护组织免受损伤。我们的研究首次揭示了 eNOS 的过表达会导致疾病进展，而非保护作用。我们将内皮细胞中选择性过表达 eNOS 的转基因小鼠（eNOSTg）与 1 型糖尿病的 Ins2Akita （AK）小鼠进行杂交，以产生过表达 eNOS 的 eNOSTg/AK 小鼠。我们对野生型、eNOSTg、AK 和 eNOSTg/AK 小鼠进行了肾功能和血糖水平的评估。值得注意的是，过表达 eNOSTg 的小鼠出现了未预料到的肾小球损伤，表现为节段性系膜溶解和偶尔出现微动脉瘤。值得注意的是，在 eNOSTg/AK 小鼠中，eNOS 的过表达导致肾小球/内皮损伤增加，这与超氧化物水平升高和肾功能障碍有关。研究结果首次表明，内皮细胞中 eNOS 的过表达不能改善糖尿病病变，但矛盾的是，它会导致肾病进展，这可能是由于 eNOS 解偶联和超氧化物激增所致。这一新发现对当前改善内皮功能和预防糖尿病肾病进展的治疗策略具有重要影响。此外，本研究中开发的 eNOSTg/AK 模型对于阐明糖尿病肾病中 eNOS 功能异常的潜在机制具有重要的转化潜力。
