The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester

Abstract

Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27–40 weeks’ gestation from women with early-onset PE (n = 20) and gestation-matched normotensive control pregnancies (n = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT), the creatine transporter (SLC6A8), and the creatine kinases (mitochondrial CKMT1A & cytosolic BBCK) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings; total creatine content of PE placentae was 38% higher than controls (p < 0.01). mRNA expression of GATM (p < 0.001), GAMT (p < 0.001), SLC6A8 (p = 0.021) and BBCK (p < 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental GATM mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results suggest PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation.

Spatially Constrained Gene Regulation Identifies Key Genetic Contributions of Preeclampsia, Hypertension and Proteinuria

“…The same kidney damage in PE that causes PRO may damage the ability of the kidneys to produce sufficient creatine, and, therefore, the increased placental expression levels of GATM could be a consequence of kidney damage having occurred. 47,49 Signaling pathways are the predominant pathways enriched for in the PPINs…”

Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health

“…Similarly, in PE placentae, total creatine content has been reported to increase by 38%, with GATM , GAMT , SLC6A8 and CKBB mRNA expression also significantly increased compared to gestational age-matched controls, although, again, these differences were not observed at a protein level [ 14 ]. There is evidence that, in the case of PE, this additional creatine may be transported to the compromised fetus, with a recent study by Jääskeläinen et al (2018) reporting an increase in creatine concentration in venous cord plasma from PE pregnancies [ 71 ].…”

“…Some interesting correlations were also observed in healthy control placentae throughout these collective retrospective studies, with placental GATM mRNA expression and GAA tissue content decreasing with advancing gestational age and birth weight. These adaptations associated with placental senescence were not observed in FGR or PE placentae, indicating an ongoing reliance on the creatine kinase circuit for placental bioenergetics in compromised pregnancies [ 13 , 14 ]. It is interesting to note that GATM , the gene that expresses AGAT, has been identified as a maternally imprinted gene, and thus is exclusively expressed in placental tissue from the maternal allele [ 72 ].…”

“…There is now strong evidence that alterations to creatine homeostasis occur with the normal progression of a healthy female reproductive cycle and with pregnancy [ 11 , 12 ]. Altered creatine metabolism has also been linked to reduced fertility and specific pregnancy-related pathologies [ 13 , 14 ]; however, there is no clear consensus as to whether creatine metabolism is indeed an essential component of bioenergetics for successful reproduction.…”

Special Issue “Molecular and Cellular Mechanisms of Preeclampsia”

“…It is a fascinating journey through the complex world of science, all meant to add another piece to the picture. The original papers range from new technologies for identifying changes in the maternal system to putative new therapies, the effect of the syndrome on the placenta, rodent models of preeclampsia, effects of the syndrome on the cardiovascular system, sex-specific differences and the effect on the children born from a preeclamptic pregnancy [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. The reviews of this Special Issue range from immunoregulation and macrophages during preeclampsia and molecular targets of therapeutics to trophoblast invasion, uterine blood flow and angiogenesis, they touch on specific protein families and oxidative stress related to preeclampsia, and finally deal with autophagy in preeclampsia and the role of epigenetics in the etiology of the syndrome [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”