Klotho in pregnancy and intrauterine development-potential clinical implications: a review from the European Renal Association CKD-MBD Working Group

Abstract

Intrauterine development is crucial for life-long health; therefore, elucidation of its key regulators is of interest for their potential prognostic and therapeutic implications. Originally described as a membrane-bound anti-aging protein, Klotho has evolved as a regulator of numerous functions in different organ systems. Circulating Klotho is generated by alternative splicing or active shedding from cell membranes. Recently, Klotho was identified as a regulator of placental function, and while Klotho does not cross the placental barrier, increased levels of circulating α-Klotho have been identified in umbilical cord blood compared with maternal blood, indicating that Klotho may also play a role in intrauterine development. In this narrative review, we discuss novel insights into the specific functions of the Klotho proteins in the placenta and in intrauterine development, while summarizing up-to-date knowledge about their structures and functions. Klotho plays a role in stem cell functioning, organogenesis and haematopoiesis. Low circulating maternal and foetal levels of Klotho are associated with preeclampsia, intrauterine growth restriction, and an increased perinatal risk for newborns, indicating a potential use of Klotho as biomarker and therapeutic target. Experimental administration of Klotho protein indicates a neuro- and nephroprotective potential, suggesting a possible future role of Klotho as a therapeutic agent. However, the use of Klotho as intervention during pregnancy is as yet unproven. Here, we summarize novel evidence, suggesting Klotho as a key regulator for healthy pregnancies and intrauterine development with promising potential for clinical use.

Keywords: Klotho; organogenesis; placenta; preeclampsia.

Figure 1:

Summary of the molecular basis, physiological and pathophysiological impacts of the Klotho proteins on pregnancy and prenatal development. Klotho's physiological role in prenatal development is summarized in the upper part of the figure. The effects of Klotho deficiency on pregnancy-associated diseases and foetal health are shown in the bottom part of the figure. Potential functions are shown on the right side of the figure. α-Klotho decreases oxidative stress and prevents aging of placenta by suppressing IGF1 signalling. Placental aging disrupts placental circulation and predisposes to pre-eclampsia in mothers and SGA in newborns. α-Klotho is involved in neurogenesis, most notably the development of foetal hippocampus. Moreover, α-Klotho increases VEGF expression and stimulates vasculogenesis and tubulogenesis in the foetal kidney. Additionally, α-Klotho is required for normal haematopoiesis. Through activation of FGF23, α-Klotho controls calcium and phosphate metabolism in intrauterine life. α-Klotho inhibits Wnt/β-catenin and HIF pathways with yet clinically undetermined effects in embryogenesis and organogenesis. β-Klotho is primarily secreted in the yolk sac in the prenatal period. As co-factor to FGF21 and FGF15, β-Klotho helps to maintain lipid and carbohydrate homeostasis and foetal–maternal cholesterol transport. Insufficiency of the β-Klotho–FGF15 axis promotes intrauterine growth restriction.