Translational Experimental Pediatrics-Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University Hospital Cologne, 50931 Cologne, Germany.
Department of Medicine II, Nephrology Research Laboratory, University Hospital of Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
Int J Mol Sci. 2023 Jan 28;24(3):2508. doi: 10.3390/ijms24032508.
Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of , revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.
慢性肾脏病（CKD）是一种全球健康负担，与年龄相关的肾功能下降、高血压和糖尿病密切相关，而这些都是肥胖的常见后果。尽管进行了广泛的研究，但决定易患 CKD 的机制仍了解不足。临床证据和我们小组之前的研究表明，宫内生长受限或母体肥胖后的围产期代谢紊乱会对整个生命周期的肾脏结构和功能产生不利影响。由于肥胖和衰老过程在相似的途径中汇聚，我们测试了宫内肥胖是否会使高脂肪饮食（HFD）喂养的母鼠引起的与衰老相关的机制敏感化新生小鼠肾脏。结果显示，γH2AX 阳性细胞数量明显增加，8-Oxo-dG（RNA/DNA 损伤）水平升高，这两者均表明存在 DNA 损伤反应和氧化应激。使用无偏综合转录组学，我们在围产期肥胖后的肾脏中鉴定了特定部位差异调节的信号通路。将这些数据与自然衰老肾脏和遗传修饰小鼠的过早衰老肾脏的转录组数据进行比较，揭示了相似的特征，例如炎症信号。在生化方法中，我们验证了围产期肥胖后肾脏中 信号通路。总之，我们的初步发现表明，围产期肥胖会导致与衰老相关的过早发生的过程，这可能会在生命早期决定 CKD 的易感性。
