| Institution: | 1. Division of Nephrology and Hypertension, University of Bern and University Hospital Bern, Bern, Switzerland;2. Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria;3. University Medical Center Hamburg-Eppendorf, III. Medizinische Klinik und Poliklinik, Hamburg, Germany;4. Centre for Physical Activity Research (CFAS), Rigshospitalet Section 7641, Copenhagen, Denmark;5. Faculty of Social and Health Sciences, Section for Health and Exercise Physiology, Inland Norway University of Applied Sciences, Lillehammer, Norway |
| Abstract: | Hypoxia-induced intrauterine growth restriction increases the risk for cardiovascular, renal, and other chronic diseases in adults, representing thus a major public health problem. Still, not much is known about the fetal mechanisms that predispose these individuals to disease. Using a previously validated mouse model of fetal hypoxia and bottom-up proteomics, we characterize the response of the fetal kidney to chronic hypoxic stress. Fetal kidneys exhibit a dichotomous response to chronic hypoxia, comprising on the one hand cellular adaptations that promote survival (glycolysis, autophagy, and reduced DNA and protein synthesis), but on the other processes that induce a senescence-like phenotype (infiltration of inflammatory cells, DNA damage, and reduced proliferation). Importantly, chronic hypoxia also reduces the expression of the antiaging proteins klotho and Sirt6, a mechanism that is evolutionary conserved between mice and humans. Taken together, we uncover that predetermined aging during fetal development is a key event in chronic hypoxia, establishing a solid foundation for Barker’s hypothesis of fetal programming of adult diseases. This phenotype is associated with a characteristic biomarker profile in tissue and serum samples, exploitable for detecting and targeting accelerated aging in chronic hypoxic human diseases. |
