Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and mortality, and its prevalence is 4 fold higher in women with diabetes than those without: the underlying mechanism is unclear. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt1) plays a key role in PE pathogenesis. Evidence suggests that PKC activation, which is associated with the development of diabetic vascular complications, may mediate the enhanced sFlt1 release in non-trophoblast cells. We aimed to determine the role of PKC in the regulation of sFlt1 expression in placental trophoblasts, and whether diabetic conditions upregulate sFlt1 expression via the PKC pathway. Human trophoblasts HTR8/SVneo were treated in three separate experiments with PKC activator phorbol-12-myristate-13-acetate (PMA), or diabetes stimuli ’heavily oxidized, glycated’ low-density lipoproteins (HOG-LDL) vs. native LDL ± high glucose (30 mM), over 24h, with or without PKC inhibitor GF109203X (GX). Both sFlt1 mRNA expression (RT-PCR) and protein release (ELISA) were measured. Compared to the control, PMA (5 nM) increased sFlt1 mRNA expression (2.5 fold, p<0.001) and protein release (383.8 ± 27.4 vs. 118.3 ± 21.3 pg/ml, p<0.001) in trophoblasts; these effects were entirely abrogated by the pre-treatment with 5 uM GX for mRNA expression (by 54%, p<0.001) and protein release (115.5 ± 20.9 pg/ml, p<0.001) vs. PMA-treated cells. Similarly, HOG-LDL (50 µg/ml) increased sFlt1 mRNA expression (3.7 fold, p<0.001) and protein release (126.4 ± 16.3 vs. 55.1 ± 2.4 pg/ml, p<0.001), and the both effects were partially abolished by GX (by 33-37%, p<0.05). High glucose did not significantly affect sFlt1 expression, or alter the effect of HOG-LDL. The data suggest that modified lipoproteins may promote PE development in women with diabetes, at least in part via PKC-mediated upregulation and release of sFlt1. These findings provide new insights into disease mechanisms, and may lead to new targets for prevention and treatment of PE.


R.P. Chow: None. J. Zhao: None. J. Yu: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at