Lasaitiene Daina, Chen Yun, Mildaziene Vida, Nauciene Zita, Sundelin Birgitta, Johansson Bengt R, Yano Masato, Friberg Peter
Dept. of Clinical Physiology, Univ. of Gothenburg, S-413 45 Gothenburg, Sweden.
Am J Physiol Renal Physiol. 2006 May;290(5):F1260-9. doi: 10.1152/ajprenal.00150.2005. Epub 2005 Oct 25.
Pharmacological interruption of the angiotensin II (ANG II) type 1 receptor signaling during nephrogenesis in rats perturbs renal tubular development. This study aimed to further investigate tubular developmental defects in neonatal rats subjected to ANG II inhibition with enalapril. We evaluated tubular ultrastructural changes using electron microscopy and estimated spectrophotometrically activity or concentrations of succinate dehydrogenase (SDH), cytochromes a and c, which are components of mitochondrial respiratory chain, on postnatal days 2 and 9 (PD2 and PD9). Renal expression of sodium-potassium adenosinetriphosphatase (Na(+)-K(+)-ATPase) and two reflectors of mitochondrial biogenesis [mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20)] also were studied using Western immunoblotting and immunohistochemistry. Enalapril disrupted inner mitochondrial membranes of developing cortical and medullary tubular cells on PD2 and PD9. These findings were paralleled by impaired mitochondrial respiratory function, as revealed from the changes in components of the mitochondrial respiratory chain, such as decreased cytochrome c level in the cortex and medulla on PD2 and PD9, decreased cytochrome a level in the cortex and medulla on PD2, and diminished cortical SDH activity on PD2 and PD9. Moreover, tubular expression of the most active energy-consuming pump Na(+)-K(+)-ATPase was decreased by enalapril treatment. Renal expression of TFAM and TOM20 was not altered by neonatal enalapril treatment. Because nephrogenesis is a highly energy-demanding biological process, with the energy being utilized for renal growth and transport activities, the structural-functional alterations of the mitochondria induced by neonatal enalapril treatment may provide the propensity for the tubular developmental defect.
在大鼠肾发生过程中，对血管紧张素II（ANG II）1型受体信号进行药理学阻断会扰乱肾小管发育。本研究旨在进一步探究用依那普利抑制ANG II的新生大鼠的肾小管发育缺陷。我们在出生后第2天和第9天（PD2和PD9），使用电子显微镜评估肾小管超微结构变化，并通过分光光度法估算线粒体呼吸链组分琥珀酸脱氢酶（SDH）、细胞色素a和c的活性或浓度。还使用蛋白质免疫印迹法和免疫组织化学法研究了钠钾三磷酸腺苷酶（Na(+)-K(+)-ATPase）的肾脏表达以及线粒体生物发生的两个标志物[线粒体转录因子A（TFAM）和线粒体外膜转位酶20（TOM20）]。依那普利在PD2和PD9破坏了发育中的皮质和髓质肾小管细胞的线粒体内膜。这些发现与线粒体呼吸功能受损相平行，这从线粒体呼吸链组分的变化中可以看出，如PD2和PD9时皮质和髓质中细胞色素c水平降低、PD2时皮质和髓质中细胞色素a水平降低以及PD2和PD9时皮质SDH活性降低。此外，依那普利治疗降低了最活跃的耗能泵Na(+)-K(+)-ATPase的肾小管表达。新生大鼠依那普利治疗未改变TFAM和TOM20的肾脏表达。由于肾发生是一个能量需求很高的生物学过程，能量用于肾脏生长和转运活动，新生大鼠依那普利治疗诱导的线粒体结构功能改变可能是肾小管发育缺陷的倾向原因。
