Reduced renal responsiveness to vasopressin during preeclampsia
Authors: Chen Kevin , Zhang Shao Yang , Scroggins Sabrina M , Deng Guorui , Sandgren Jeremy A , Zepeda‐Orozco Diana , Pierce Gary L , Santillan Mark K , Grobe Justin L , Santillan Donna Ann 
Published: June 2021

Preeclampsia (PE), a devastating cardiovascular disorder of pregnancy, is characterized by altered uterine artery function near the end of the first trimester, altered angiogenic factors and placental hypoxia in mid‐gestation, and a constellation of clinical features in the second half of gestation often including new onset hypertension, proteinuria, and intrauterine growth restriction. We and others have demonstrated that maternal plasma concentrations of copeptin (CPP), the C‐terminal fragment of arginine vasopressin (AVP) that is used as a stable and reliable marker of AVP secretion, is increased throughout gestation, at least as early as the sixth week of gestation. Further, we have demonstrated that AVP infusion into pregnant mice is sufficient to model the clinical features of PE. As plasma osmolality is normal during PE, we hypothesized that AVP secretion is increased during PE in response to reduced renal sensitivity to AVP. We analyzed urine collected from n=40 PE and n=40 age (30.9±0.7 vs 29.2±0.8 years; mean±SEM) and gestational age (13.2±0.6 vs 13.0±0.4 week)‐matched control human pregnancies, collected by the University of Iowa Maternal‐Fetal Tissue Bank. CPP to total protein ratio was increased in urine (median(quartiles): 29(18–47) vs 49(30–83) ng/g, p<0.05 by Mann‐Whitney U), which was appropriately associated with increased shedding of aquaporin‐2 to the urine (AQP2; 0.7(0.4–1.5) vs 1.1(0.7–2.0) ug/g, p<0.05), resulting in a normal AQP2/CPP ratio (26(13–50) vs 25(16–40), p=0.98). Supporting our working hypothesis, no increase in urine osmolality (mean±SEM: 473±45.8 vs 471.2±51.1 mOsm/kg H2O) was observed. As these urine samples were collected near the end of the first trimester, it is unsurprising that proteinuria was not yet established (5.57±0.57 vs 5.71±0.68 mg/mL). This cohort of women with PE were characterized by increased BMI, a typical risk factor for PE (27.7±1.1 vs 35.7±1.5 kg/m2, p<0.05 by t‐test), which may help explain the observed increase in CPP; yet it is unclear whether BMI modulates renal AVP responsiveness and AQP2 regulation. In summary, PE is associated with increased urinary CPP and AQP2 but normal osmolality in early pregnancy, before onset of major clinical features. These findings support the hypothesis that elevated AVP secretion during PE is secondary to reduced renal responsiveness to AVP. Investigation of renal sensitivity to AVP in early pregnancy, or perhaps pre‐pregnancy, as a predictor and preventative therapeutic target for PE, is warranted.Support or Funding InformationFunding provided by The American Physiological Society Undergraduate Summer Research fellowship (KC), The American Physiological Society Undergraduate Research fellowship (SZ), American Heart Association Postdoctoral Fellowship (SS), American Heart Association Strategically Focused Research Network in Hypertension (MS, JG, SS, DS, GD).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.