Imbalance of Sphingolipids Synthesis/Degradation Pathway in Preeclamptic Mouse Placenta and Kidney of Intrauterine Growth Restricted Mouse Fetus

Abstract

Preeclampsia (PE) is a pregnancy hypertensive disorder that results in intrauterine growth restriction (IUGR) of the offspring. Adult IUGR individuals have increased risks of developing cardiovascular and renal diseases due to poor kidney development during embryonic stage. The treatment of PE remains ineffective and the mechanism of PE‐induced poor kidney growth of IUGR fetus has not been conclusive leading to a persistent clinical challenge. Bioactive sphingolipids ceramide (Cer) and sphingosine‐1‐phosphate (S1P) function as key regulators of cellular homeostasis. The reduced levels of circulating angiogenic S1P and elevated levels of pro‐apoptotic Cer have been demonstrated in PE women. Ceramidase hydrolyzes Cer to produce sphingosine. Sphingosine can then be phosphorylated by sphingosine kinase (Sphk) 1 and 2 to form S1P. Whether sphingolipids and sphingolipids‐related protein implicate as potential key factors involved in the pathogenesis of PE and nephrogenesis in IUGR fetus is unknown. Here, we tested the hypothesis that the synthesis/degradation pathway of S1P and Cer is altered in PE placenta and kidneys of IUGR fetus. We used reduced uterine perfusion (RUP) mouse model to represent PE in this study. C57bl/6J mice underwent sham or RUP surgeries at day 13 of gestation. At day 18 of gestation, placentas from both sham (control) and RUP mice, as well as kidneys from control and IUGR pups were collected. Using commercial ELISA kits, S1P in RUP placenta was significantly lower than in sham placenta (P<0.05, n=3) despite no significant difference was found between control and IUGR pup kidneys. mRNA levels was measured using qRT‐PCR and GAPDH was used as the control housekeeping gene. Placenta results (n=5): mRNA of neutral ceramidase (Asah2) and alkaline ceramidase 2 (Acer2) but not acid ceramidase (Asah1) were three folds lower in RUP placentas suggesting the conversion of Cer to sphingosine is impaired in RUP. Lower conversion from sphingosine to S1P as the level of sphingosine kinase ‐2 (Sphk‐2) was significantly decreased in RUP placentas. Significantly lower in ceramide kinase (Cerk), and S1P phosphatase 2 (Sgpp2) mRNA levels were also observed in RUP. These data suggest that the synthesis and degradation pathways of S1P in RUP placentas are decreased which coincide with the lower angiogenic S1P. Pup kidneys results (n=7): Asah2 and Acer2 were two‐fold decreased in IUGR kidneys (P<0.05). No significant difference of Asah1, Sphk1, Sphk2, Cerk, and Sgpp2 was found between control and IUGR. However, S1P receptor 1 (S1PR1), that plays important role in nephrogenesis, was significantly lower in IUGR kidneys. We conclude that the alteration of synthesis and degradation pathways of S1P in placentas may play a role in PE pathology. Lower in Asah2, Acer2 and S1PR1 may underlie the impairment of nephrogenesis in IUGR which will impact the renal health in later of life.Support or Funding InformationDr. Intapad was supported by funding from the AHA 16SDG27770041, ASN Kidney Research Career Development grant, and Start‐up funds from Tulane University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.