Pre-eclampsia is a principal cause of maternal morbidity and mortality, affecting 5-10% of first pregnancies worldwide. Manifestations include increased blood pressure, proteinuria, coagulopathy and peripheral and cerebral oedema. Although the aetiology and pathogenesis remain to be elucidated, the placenta is undoubtedly involved, as termination of pregnancy eradicates the disease. Here we have cloned a complementary DNA from human placental messenger RNA encoding a precursor protein of 121 amino acids which gives rise to a mature peptide identical to the neuropeptide neurokinin B (NKB) of other mammalian species. In female rats, concentrations of NKB several-fold above that of an animal 20 days into pregnancy caused substantial pressor activity. In human pregnancy, the expression of NKB was confined to the outer syncytiotrophoblast of the placenta, significant concentrations of NKB could be detected in plasma as early as week 9, and plasma concentrations of NKB were grossly elevated in pregnancy-induced hypertension and pre-eclampsia. We conclude that elevated levels of NKB in early pregnancy may be an indicator of hypertension and pre-eclampsia, and that treatment with certain neurokinin receptor antagonists may be useful in alleviating the symptoms.
The expression and activities of corticotrophinreleasing factor (CRF), urocortin (UCN), the CRF-binding protein (CRF-BP) and CRF receptors in rat brain have been well documented; however, information regarding their peripheral distributions remains incomplete. Given the multiple immunomodulatory effects of peripherally administered CRF and UCN and the high levels of CRF receptor type 2 (CRF-R2) mRNA and protein expressed in the heart, the lymphoid organs and heart have become targets for some of the latest CRF-related research. Here we demonstrate the presence of UCN mRNA in both the rat spleen and human Jurkat T-lymphoma cells using 3 -RACE (rapid amplication of cDNA ends) PCR. Following on from these initial results, we used semiquantitative RT-PCR to carry out a comprehensive study assessing the relative amounts of CRF, UCN, CRF-R1, CRF-R2 and CRF-BP mRNAs in the brain, thymus, spleen and heart of normal, untreated rats. The rank orders of mRNA abundance in each of the tissue types were as follows: for CRF, brain> >thymus=spleen=heart; for UCN, heartdbrain>thymus>spleen; for CRF-R1, brain> >thymus>spleen (absent in heart); for CRF-R2, brain=heart>thymus>spleen; and CRF-BP was only detectable in the brain. We have provided evidence for the existence of CRF, UCN, CRF-R1 and CRF-R2 expression in resting immune cells, with UCN expression being particularly predominant in the rat thymus and human Jurkat cells. Additionally, the high levels of UCN mRNA detected in heart corresponded to the high expression of CRF-R2 mRNA, suggesting an important role for UCN/CRF-R2 coupling in this tissue.
SUMMARY
Late gestational maternal plasma contains a carrier substance for corticotrophin releasing factor (CRF‐41) with a molecular weight in the region of 40000. Using gel chromatography and CRF‐41 immunoradiometric assay (IRMA), we show that binding of the peptide to its plasma carrier can be disrupted by treatment with urea. The binding capacity of the carrier substance is not saturated, since time‐dependent incorporation of synthetic CRF‐41 occurs at 4°C. The carrier substance is also present in normal male plasma. It is specific for human CRF‐41, not binding to ACTH, GnRH, vasopressin or ovine CRF‐41. Most of the high concentration of CRF‐41 in late gestational maternal plasma is bound to the carrier. Dilutions of pooled fractions containing carrier‐bound CRF‐41 after chromatography of maternal plasma had ACTH‐releasing activity as did the synthetic peptide. However, the more concentrated chromatographic fractions at the apex of the carrier‐bound CRF‐41 peak showed reduced bioactivity, indicating that the higher concentrations of carrier in the original maternal plasma could mask the ACTH‐releasing activity of CRF‐41.
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