Department of Nephrology and Hypertension, Bern University Hospital, Freiburgstrasse 15, 3010, Bern, Switzerland.
Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland.
Nat Commun. 2021 Jan 22;12(1):549. doi: 10.1038/s41467-020-20832-7.
Intrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.
宫内生长受限（IUGR）与出生时肾脏缩小、肾功能下降加速以及成年人患慢性肾脏和心血管疾病的风险增加有关。胎儿编程导致成人疾病的确切机制在很大程度上仍难以捉摸，需要广泛研究。本研究通过建立缺氧诱导的 IUGR 小鼠模型，以肾脏为研究对象，对 mRNA、蛋白质和细胞水平的胎儿适应及其长期功能后果进行了特征描述。在这里，我们确定胎球蛋白-A 是一种进化保守的 HIF 靶基因，并进一步使用胎球蛋白-A KO 动物和缺血再灌注损伤的成年模型来研究其作用。除了作为全身性钙化抑制剂的作用外，胎球蛋白-A 还作为一种多效性保护因子出现，局部抑制钙化、调节巨噬细胞极化，并减轻炎症和纤维化，从而保护肾脏功能。我们的研究为减轻矿物质应激诱导的炎症和损伤的治疗方法铺平了道路，主要适用于所有软组织。
