Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia

Abstract

Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.

1. Introduction

Preeclampsia (PE) is a pregnancy disorder characterized by hypertension that occurs in approximately 5% of pregnancies and ranks among the primary causes of maternal and perinatal mortality worldwide [1]. This condition is marked by the development of high blood pressure after 20 weeks of pregnancy, along with the presence of proteinuria and/or acute kidney injury in the mother. Additionally, it may be accompanied by liver dysfunction, neurological complications, thrombocytopenia or hemolysis, as well as fetal growth restriction [2,3]. Despite extensive research efforts and advancements in clinical management, the underlying mechanisms of PE remain elusive, and no effective treatment options other than delivery are currently available [4].

Autophagy is a highly conserved cellular process observed in organisms ranging from yeast to mammals, and it serves to preserve cellular homeostasis in response to stress [5]. Initially, autophagy was shown to function as a means of generating energy during periods of starvation [6]. Indeed, a wealth of evidence suggests that autophagy has a multitude of functions, including stress protection, energy regulation, immune modulation, cellular differentiation, proliferation, and programmed cell death [7‒9]. Recent studies have demonstrated an increase in autophagy in placentas affected by complications such as PE or foetal growth restriction [10]. Furthermore, there is a positive correlation between the severity of these conditions and increased formation of autophagosomes, suggesting that abnormal autophagic activity is one of the underlying mechanisms responsible for compromised trophoblast invasion [11]. 3-Methyladenine (3-MA) is a recognized phosphatidylinositol 3-kinase (PI3K) inhibitor and an autophagy modulator [12]. 3-MA can reportedly induce cell death in cancer cells through both autophagy-dependent and autophagy-independent pathways [13]. Nonetheless, comprehensive research investigating the potential of 3-MA as an inhibitor of PE progression is scarce.