Lactic Acid Transport Mediated by Aquaporin-9: Implications on the Pathophysiology of Preeclampsia

Abstract

Aquaporin-9 (AQP9) expression is significantly increased in preeclamptic placentas. Since feto-maternal water transfer is not altered in preeclampsia, the main role of AQP9 in human placenta is unclear. Given that AQP9 is also a metabolite channel, we aimed to evaluate the participation of AQP9 in lactate transfer across the human placenta. Explants from normal term placentas were cultured in low glucose medium with or without L-lactic acid and in the presence and absence of AQP9 blockers (0.3 mM HgCl2 or 0.5 mM Phloretin). Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release. Apoptotic indexes were analyzed by Bax/Bcl-2 ratio and Terminal Deoxynucleotidyltransferase-Mediated dUTP Nick-End Labeling assay. Heavy/large and light/small mitochondrial subpopulations were obtained by differential centrifugation, and AQP9 expression was detected by Western blot. We found that apoptosis was induced when placental explants were cultured in low glucose medium while the addition of L-lactic acid prevented cell death. In this condition, AQP9 blocking increased the apoptotic indexes. We also confirmed the presence of two mitochondrial subpopulations which exhibit different morphologic and metabolic states. Western blot revealed AQP9 expression only in the heavy/large mitochondrial subpopulation. This is the first report that shows that AQP9 is expressed in the heavy/large mitochondrial subpopulation of trophoblasts. Thus, AQP9 may mediate not only the lactic acid entrance into the cytosol but also into the mitochondria. Consequently, its lack of functionality in preeclamptic placentas may impair lactic acid utilization by the placenta, adversely affecting the survival of the trophoblast cells and enhancing the systemic endothelial dysfunction.

Space Environment Impacts Homeostasis: Exposure to Spaceflight Alters Mammary Gland Transportome Genes

“…These two AQPs are identified as aquaglyceroporins that mediate H 2 O and glycerol trafficking [81]. Also, a recent study reveals that AQP9 facilitates monocarboxylates passage into the cytosol and mitochondria [82]. Dysregulation of AQP3 and AQP9 impairs osmoregulation, energy production, and removal of ROS [83,84], which would likely alter mammary function.…”

Hypoxic Microenvironment Promotes PTBP1 Lactonization and IGF2BP2 Read Defects Mediate the Development of Preeclampsia

“…All of the above studies imply that lactate may play a crucial role in the microenvironment of PE patients. Although the work of Yollyseth Medina et al confirmed that CTB hypoxia in PE patients activates anaerobic glycolysis leading to a functional defect in lactate transport proteins, which in turn leads to excessive lactate accumulation and promotes excessive protein lactation (19)(20)(21). However, the effect of hypoxia-induced protein hyperlactivation on PE has never been explored.…”