Department Medical Cell Biology, Div. Integrative Physiology, Uppsala University, Biomedical Center, D1:3, Husargatan 3, 571, SE-751 23, Uppsala, Sweden.
Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Adv Exp Med Biol. 2013;789:9-14. doi: 10.1007/978-1-4614-7411-1_2.
Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.
肾内组织缺氧是一种公认的常见途径，可导致临床常见的与慢性肾脏病发展相关的终末期肾脏疾病，如糖尿病和高血压。在糖尿病肾脏中，由线粒体解偶联介导的氧代谢增加导致肾脏氧张力（PO2）降低，并导致糖尿病肾病的发展。本研究旨在探讨增加的肾内氧代谢本身是否可以导致肾内组织缺氧和肾脏损伤，而不考虑高血糖和氧化应激等混杂因素。雄性 Sprague-Dawley 大鼠未处理或用三碘甲状腺原氨酸（T3，10 g/kg bw/天，皮下注射 10 天）或线粒体解偶联剂二硝基苯酚（DNP，30 mg/kg bw/天，口服灌胃 14 天）处理，然后评估体内肾功能肾小球滤过率（GFR，菊粉清除率）、肾血流量（RBF，Transonic，PAH 清除率）、皮质 PO2（Clark 型电极）、肾氧耗量（QO2）和蛋白尿。T3 和 DNP 的联合给药增加了肾脏 QO2 并降低了 PO2，导致蛋白尿。然而，GFR 和 RBF 不受任何治疗的影响。本研究表明，增加的肾脏代谢本身可以导致肾内组织缺氧，从而导致蛋白尿。因此，增加的肾脏 QO2 和随之而来的 PO2 降低可能是慢性肾脏病发展和终末期肾脏疾病进展的机制。
