Circulating and Placental Growth-Differentiation Factor 15 in Preeclampsia and in Pregnancy Complicated by Diabetes Mellitus

Abstract

Growth-differentiation factor 15 (GDF-15), a stress-responsive transforming growth factor-β–related cytokine, is emerging as a new risk marker in patients with cardiovascular disease. We explored GDF-15 in preeclampsia and in diabetic pregnancies, because these conditions are associated with augmented risk for cardiovascular disease, both in mother and in offspring. Plasma from pregnant women (n=267; controls: n=59, preeclampsia: n=85, diabetes mellitus: n=112, and superimposed preeclampsia in diabetes mellitus: n=11), fetal plasma (n=72), and amniotic fluid (n=99) were analyzed by immunoassay for GDF-15. Placental GDF-15 mRNA and protein expression levels were analyzed by quantitative real-time PCR and immunoblots in 78 and 18 pregnancies, respectively. Conditioned media from preeclamptic (n=6) and control (n=6) villous placenta explants were analyzed by immunoassay for GDF-15. Median maternal GDF-15 concentration was elevated in those with diabetes mellitus, as compared with controls (91 549 versus 79 875 ng/L; P=0.02). Median GDF-15 concentration was higher in patients with preeclampsia than in controls in term maternal blood samples (127 061 versus 80 319 ng/L; P<0.001). In the fetal circulation and amniotic fluid, GDF-15 was elevated in preeclampsia and superimposed preeclampsia in diabetes mellitus, as compared with controls. GDF-15 placental mRNA expression was elevated in preeclampsia, as compared with controls (P=0.002). Placenta immunoblots confirmed a single GDF-15 protein band, and a time-dependent increase in GDF-15 protein was detected in the conditioned media. Our study is the first to show that GDF-15 is dysregulated, both in preeclampsia and in diabetic pregnancies. The mechanisms and diagnostic implications of these findings remain to be explored.

Growth Differentiation Factor-15 as Biomarker in Uterine Sarcomas

“…17 Growth differentiation factor-15 is normally highly expressed in the placenta, 18 but further augmented circulating GDF-15 in pregnancies have been linked to increased occurrence of preeclampsia and diabetes mellitus, both conditions correlated to increased risk for cardiovascular disease. 19 We did not find significantly higher GDF-15 concentrations in the higher age groups, suggesting only weak effects of potentially confounding factors related to comorbidities known to increase with age. We also applied disease-specific survival as outcome measure to minimize any confounding effects related to cardiovascular deaths in our study.…”

A comprehensive analysis of the human placenta transcriptome

“…HTRA1 was also highly expressed with a RPKM of ~300. HTRA1 encodes a peptidase that may play a role in the regulation of IGF bioavailability by cleaving IGF-binding proteins [10] and is dysregulated in trophoblastic diseases [11] Additionally, GDF15 is a transforming growth factor-beta (TGF-β) cytokine that has implications in cardiovascular disease and has been identified to be dysregulated in pre-eclamptic and diabetic pregnancies [12]. GDF15 also had a RPKM of >1000 and was within the top 20 expressed genes in the placenta.…”

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

“…28 Besides cardiovascular tissue, elevated GDF-15 expression has been found in patients with rheumatoid arthritis, 29 congenital anemia 30,31 and metabolic disorders, such as obesity, diabetes mellitus or preeclampsia. 32,33 In cases of ineffective hematopoiesis, GDF-15 is likely involved in iron metabolism and erythrocyte differentiation. 34 GDF-15 overexpression was measured after mechanical liver or kidney injury 35 and was capable of inducing the renewal of specific cell populations, including renal acid-secreting collecting duct cells.…”