Altered expression of p97/Valosin containing protein and impaired autophagy in preeclamptic human placenta.

ABSTRACT

INTRODUCTION: Autophagy increases in placenta-related obstetrical diseases such as preeclampsia and intrauterine growth retardation but the regulation of autophagy by ubiquitin proteasome pathway (UPP) proteins, p97/Valosin containing protein (VCP) and ubiquitin (Ub) have not been previuosly studied in preeclampsia. The objective of this study is to investigate the expression of UPP (p97/VCP and Ub), autophagosomal (p62 and LC3) and autolysosomal proteins (Lamp1 and Lamp2) in the normal and preeclamptic human placentas and to explore the regulatory mechanism of these proteins in autophagic pathway. MATERIAL AND METHODS: Different portions of normal term placentas (n = 20) and preeclamptic placentas (n = 10) were snap-frozen in liquid nitrogen for Western blotting and coimmunoprecipitation and others were fixed-embedded in paraffin for immunohistochemistry. Colocalization and coimmunoprecipitation experiments were done for the detection of interaction between p97/VCP and autophagic proteins. RESULTS: Compared with normal placentas, expression of p97/VCP was significantly reduced; however accumulation of ubiquitinlated proteins were significantly increased in preeclamptic placentas. The expression of autophagosomal proteins (LC3-II and p62) were significantly increased and no significant alterations of the expression of autolysosomal proteins were observed in preeclamptic placentas. Additionally, p97/VCP was found to colocalized and interact with autophagosomal and autolysosomal markers in normal and preeclamptic placentas. Autophagosome maturation diminished and autophagosomes had decreased localization with lysosomal markers in preeclamptic human placentas. CONCLUSION: Decreased expression of p97/VCP and increased expression of Ub in preeclampsia might be related to impaired autophagy and pathophysiology of preeclampsia. Therefore, our study highlights an important potential relationship between p97/VCP and autophagic proteins in preeclampsia.