Stangenberg Stefanie, Nguyen Long T, Chen Hui, Al-Odat Ibrahim, Killingsworth Murray C, Gosnell Martin E, Anwer Ayad G, Goldys Ewa M, Pollock Carol A, Saad Sonia
Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia.
School of Medical and Molecular Biosciences, Faculty of Science, Centre for Health Technology, University of Technology, Sydney, Australia.
Int J Biochem Cell Biol. 2015 Jul;64:81-90. doi: 10.1016/j.biocel.2015.03.017. Epub 2015 Apr 4.
An adverse in-utero environment is increasingly recognized to predispose to chronic disease in adulthood. Maternal smoking remains the most common modifiable adverse in-utero exposure leading to low birth weight, which is strongly associated with chronic kidney disease (CKD) in later life. In order to investigate underlying mechanisms for such susceptibility, female Balb/c mice were sham or cigarette smoke-exposed (SE) for 6 weeks before mating, throughout gestation and lactation. Offspring kidneys were examined for oxidative stress, expression of mitochondrial proteins, mitochondrial structure as well as renal functional parameters on postnatal day 1, day 20 (weaning) and week 13 (adult age). From birth throughout adulthood, SE offspring had increased renal levels of mitochondrial-derived reactive oxygen species (ROS), which left a footprint on DNA with increased 8-hydroxydeoxyguanosin (8-OHdG) in kidney tubular cells. Mitochondrial structural abnormalities were seen in SE kidneys at day 1 and week 13 along with a reduction in oxidative phosphorylation (OXPHOS) proteins and activity of mitochondrial antioxidant Manganese superoxide dismutase (MnSOD). Smoke exposure also resulted in increased mitochondrial DNA copy number (day 1-week 13) and lysosome density (day 1 and week 13). The appearance of mitochondrial defects preceded the onset of albuminuria at week 13. Thus, mitochondrial damage caused by maternal smoking may play an important role in development of CKD at adult life.
子宫内不良环境越来越被认为是成年后患慢性病的诱因。母亲吸烟仍然是最常见的可改变的子宫内不良暴露因素，会导致低出生体重，而低出生体重与晚年慢性肾脏病（CKD）密切相关。为了研究这种易感性的潜在机制，在交配前、整个妊娠期和哺乳期，对雌性Balb/c小鼠进行了6周的假手术或香烟烟雾暴露（SE）。在出生后第1天、第20天（断奶）和第13周（成年期），对后代的肾脏进行氧化应激、线粒体蛋白表达、线粒体结构以及肾功能参数的检测。从出生到成年，SE组后代肾脏中线粒体衍生的活性氧（ROS）水平升高，这在肾小管细胞中留下了DNA印记，8-羟基脱氧鸟苷（8-OHdG）增加。在第1天和第13周时，SE组肾脏出现线粒体结构异常，同时氧化磷酸化（OXPHOS）蛋白减少，线粒体抗氧化剂锰超氧化物歧化酶（MnSOD）活性降低。烟雾暴露还导致线粒体DNA拷贝数增加（第1天至第13周）和溶酶体密度增加（第1天和第13周）。线粒体缺陷的出现早于第13周蛋白尿的发生。因此，母亲吸烟引起的线粒体损伤可能在成年期CKD的发展中起重要作用。
