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Abstract: TH-PO742

Feto-Maternal Cross-Talk via Extracellular Vesicles and Sterile Inflammation During Preeclampsia Reprograms the Offspring for Increased Risk of Anti-GBM Disease

Session Information

Category: Women’s Health and Kidney Diseases

  • 2000 Women’s Health and Kidney Diseases

Authors

  • Kohli, Shrey, Otto-von-Guericke University Madgeburg, Magdeburg, Germany
  • Gupta, Anubhuti, Otto-von-Guericke University Madgeburg, Magdeburg, Germany
  • Krishnan, Shruthi, Otto-von-Guericke University Madgeburg, Magdeburg, Germany
  • Isermann, Berend Heinrich, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
Background

Gestational vascular diseases such as preeclampsia (PE) are associated with maternal and fetal morbidity and mortality. PE is often associated with intra-uterine growth restriction (IUGR) predisposing for diseases later in life. We have shown that maternal extracellular vesicles (EVs) and platelets promote PE and placental sterile inflammation. We now aim to evaluate whether fetal re-programming due to EV induced pregnancy complications may predispose the offspring to an increased risk of renal diseases later in life.

Methods

EVs were injected in pregnant C57Bl/6 mice and pregnancy outcome (fetal death, IUGR, renal pathology) was studied. Proteinuria, renal histology, blood pressure and sFlt-1 was measured in the mother to establish PE-like symptoms. Embryonic and neonatal kidneys were evaluated for in-utero reprogramming. Offsprings from control and EV injected mothers were subjected to glomerulonephritis using anti-GBM serum and kidneys were studied for signs of renal disease.

Results

EV injections resulted in PE in the mother and IUGR in embryos and low birth weight. Whole embryos and neonatal kidneys from EV injected PE-mothers showed enhanced basal inflammasome activation (elevated NLRP3, cleaved IL-1β expression) indicating in-utero reprogramming. Anti-GBM serum injections into offsprings (age 8 weeks) from EV injected PE-mothers showed elevated albuminuria, impaired glomerular pathology (PAS staining), enhanced inflammasome activation, KIM-1 expression and reduced nephrin expression in kidneys compared to control offsprings (no PE) exposed to anti-GBM serum. Mechanistically, maternal EVs were taken up by trophoblast cells and reached the embryonic circulation. Maternal EVs contained bioactive cargos such as RNA and IL-1β. Importantly, exposure of EVs to RNase prior to injection or inhibition of IL-1R-signaling using anakinra abolished the inflammatory effects of maternal EVs on the embryo.

Conclusion

These results show that increased maternal EVs affect the embryo proper in addition to acute pregnancy complications. These effects on embryos persist during pregnancy and increase the risk for renal diseases in later life. Further studies are required to evaluate the mechanisms by which EVs can possibly cross the placenta predisposing the offspring to deleterious health effects.