Biomedical Basis of the Barker Hypothesis Uncovered (Medicine)

A research group from Inselspital, Universitätsspital Bern and the University of Bern has published a comprehensive study on prenatal causes of kidney disease in adults in “Nature Communications”. The finding: The serum protein fetuin-A plays a central role in coping with local inflammation and microcalcifications in the fetal kidney, which have an impact on kidney function in adulthood. The results of the study provide indications of the clinical use of Fetuin-A in kidney diseases.

According to the Barker hypothesis according to Hales and Barker, 1992 (also known as the “small baby syndrome” hypothesis), infants who are too low in body weight have an increased risk of developing cardiovascular diseases, high blood pressure, diabetes and chronic kidney disease in adulthood. According to this hypothesis, the fetal protective mechanisms allow adaptation to unfavorable intrauterine conditions (chronic oxygen or nutrient deficiency) and enable the fetus to survive. At the same time, however, they lead to permanent structural and functional loads and changes into adulthood. The extensive study recently published in “Nature Communications” now clarifies the central mechanisms of this phenomenon for the first time.

Fetuin-A plays a key role

As part of the national research focus Kidney.CH supported by the Swiss National Science Foundation, the research team has developed a mouse model that initiates a reduction in growth due to a lack of oxygen. First it was discovered that a lack of oxygen in the fetus (fetal hypoxia) causes local inflammation and microcalcifications with tissue damage in the kidney and thus a faster decline in kidney function in adulthood. The Barker hypothesis was confirmed on the basis of experimental findings. At the same time, due to the lack of oxygen, the gene for the serum protein fetuin-A is activated locally in the kidney, i.e. outside the previously known expression site. This is quite useful, as the already known function of Fetuin-A is to protect the vascular system from calcification.

Prof. Dr. med. Uyen Huynh-Do, Leitende Ärztin, Universitätsklinik für Nephrologie und Hypertonie, Inselspital, Universitätsspital Bern

The study also demonstrates numerous previously unknown functions of fetuin-A in the kidney. These include the prevention of calcification and fibrotic changes in the kidney tissue, as well as the inhibition of inflammatory processes. The research team was also able to show that Fetuin-A not only performs these functions during development, but also protects against fibrotic adhesion of the kidney tissue after an acute lack of oxygen in fully developed kidneys.

Fetuin-A with significant pharmacological potential

The versatility of the modes of action of Fetuin-A was just as surprising as the fact that the kidneys are particularly influenced by it. There is much to suggest that fetuin-A as a drug could play an important role in both kidney damage due to lack of oxygen and after reperfusion of an ischemic circulatory disorder. The first author Stefan Rudloff explains: “For us, the discovery that fetuin-A is produced in a targeted manner in the fetal kidney outside of the liver when there is a lack of oxygen was a first, surprising finding. The further we expanded the research, the clearer the importance of fetuin-A became not only in coping with damage from lack of oxygen in the fetal phase, but also in adulthood. “

Translational research and development

The research team of Prof. Dr. med. Uyen Huynh-Do and Dr. rer. nat. Stefan Rudloff at the University Clinic for Nephrology and the Department for Biomedical Research at the University of Bern can rely on very favorable local conditions. The follow-up project is funded by the Research Acceleration Initiative 2020 (RAI 2020) of the research department of CSL Behring. It is one of the three winners of the project financing within the framework of RAI 2020. The study director Prof. Uyen Huynh-Do emphasizes: “Without the funding and network of the NCCR Kidney.CH we would not have been able to carry out this study. The future close cooperation with the research department of CSL Behring as an industrial partner was also supported by sitem-insel (Swiss Institute for Translational Medicine and Entrepreneurship). In the premises of the sitem island, translational research and development is taken very seriously and actively promoted. Thanks to the proximity of the university clinic, the research facilities of the university at the DBMR and the industrial partner CSL Behring, a further, translational project could now be started that is based on the newly published research data. “

Featured image: Dr. rer. nat. Stefan Rudloff, Postdoktorand, Department for Biomedical Research (DBMR), Universität Bern ©

Reference: Rudloff, S., Janot, M., Rodriguez, S. et al. Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress. Nat Commun 12, 549 (2021).

Provided by Bern University Hospital

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