Expression and Potential Role of Peroxisome Proliferator-Activated Receptor γ in the Placenta of Diabetic Pregnancy

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed predominantly in adipose tissue and is known to be involved in adipocyte differentiation and insulin sensitivity. Recent reports indicated that PPARgamma-deficient mice were embryonic lethal due to abnormal placental development, suggesting that PPARgamma plays an important role in normal development of placenta. On the other hand, expression of vascular endothelial growth factor (VEGF), the other important factor in placental development, has been demonstrated to be regulated by PPARgamma in vascular smooth muscle cells. Also, diabetic pregnancy is often associated with defective placental functions. In order to investigate physiological roles of PPARgamma and VEGF in placental development during diabetic pregnancy, we examined the expressions of PPARgamma and VEGF in placentas, which were obtained from normal and streptozotocin-induced diabetic pregnant mouse, and studied in vitro effects of hyperglycemic condition and PPARgamma ligands (rosiglitazone and 15-deoxy-delta(12,14)prostaglandin J(2)) on trophoblasts using human choriocarcinoma cell lines. In diabetic mouse placentas (n=5), expressions of PPARgamma and VEGF proteins significantly increased as compared with these in normal placenta (n=3 or 4). In vitro studies indicated that hyperglycemic condition (42 mM) significantly enhanced the PPARgamma expression and hCG production, and significantly suppressed cell proliferation, however these effects were attenuated by PPARgamma ligands that accompanied with increased VEGF production. These data suggest that the PPARgamma pathway might be involved in the impairment of placental development induced by high glucose conditions, and that VEGF might play some roles in this pathway.

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

“…34 However, although PPAR-␥ agonists have been shown previously to restore proangiogenic factors, upregulate HO-1, 10 and increase the production of VEGF in vitro [35][36][37] and in vivo, 18 rosiglitazone failed to alter angiogenic factors in the RUPP rat in the present study. A recent study, involving the induction of HO-1 in RUPP rats via the administration of cobalt (III) protoporphyrin IX chloride, demonstrated that, as a result of cobalt (III) protoporphyrin IX chloride treatment, placental expression of HO-1 was increased, and there was a significant shift in the angiostatic balance ratio (sFlt-1:VEGF).…”

PPAR‐γ – a possible drug target for complicated pregnancies

“…PPAR-g agonists have been shown to up-regulate HO-1 expression an anti-oxidant enzyme that negatively regulates the production of the anti-angiogenic mediator, sFlt-1 (Cudmore et al, 2007;Kronke et al, 2007). Moreover PPAR-g agonists serve to increase the production of the pro-angiogenic hormone, VEGF, in macrophages, vascular smooth muscle cells and endothelial cells (Jozkowicz et al, 2000;Yamakawa et al, 2000;Inoue et al, 2001a,b;Negro et al, 2005;Suwaki et al, 2007).…”

Chronic Effects of Berberine on Blood, Liver Glucolipid Metabolism and Liver PPARs Expression in Diabetic Hyperlipidemic Rats

“…24) PPARg protein expression significantly increased in diabetic mouse placentas as compared with in normal placenta, while, PPARg ligand attenuated the significantly enhanced PPARg expression at high glucose condition. 25) But high glucose caused both PPARa mRNA and protein expression reductions in islets or INS (832/13) bcells. 26) Berberine inhibited lipid synthesis in human hepatocytes not only through elevation the low density lipoprotein receptor expression, 27) but also through the activation of AMP-activated protein kinase (AMPK).…”