Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

It is now recommended practice to use estimated glomerular filtration rate (eGFR) values to screen for and monitor chronic renal disease. The most frequently used formula in the general population is that described following the Modification of Diet in Renal Disease (MDRD) study whereby serum creatinine is adjusted for age, gender and race. This study evaluates the performance of the MDRD formula in pregnancy by comparing eGFR with measured values obtained by inulin clearance studies in early and late normal pregnancy and in pregnancies complicated by renal disease or preeclampsia. Our results indicate that in all situations, MDRD substantially underestimates glomerular filtration rate during pregnancy and cannot be recommended for use in clinical practice.

Osmoregulation was studied in eight women during late pregnancy and again 8-10 wk postpartum. Base-line plasma osmolality (Posmol) was significantly lower during (280.9 +/- 2.1 mosmol/kg, SD) than after (289.4 +/- 2.1 mosmol/kg) pregnancy yet 24-h urinary volume and plasma arginine vasopressin (PAVP) measured in vasopressinase-inactivated blood was similar in both groups (pregnancy, 1.39 +/- 0.56 pg/ml; postpartum, 1.25 +/- 0.62 pg/ml). After 12 h of dehydration PAVP rose similarly and significantly both during (2.25 +/- 0.81 pg/ml) and after (2.89 +/- 1.19 pg/ml) gestation, and Uosmol was similar on both occasions (pregnancy, 779 +/- 121 mosmol/kg; postpartum, 784 +/- 102 mosmol/kg). When Posmol was increased by the slow infusion of 5% saline PAVP increased as soon as body tonicity did both during and after pregnancy. PAVP correlated significantly with Posmol in each subject (range of r, 0.75-0.99) and the mean regression lines [pregnancy, PAVP = 0.32 (Posmol; -279), r = 0.79; postpartum, PAVP = 0.38 (Posmol, -285), r = 0.86] demonstrated that the apparent osmotic threshold for AVP secretion was 6 mosmol/kg lower during than after gestation. Similarly the Posmol at which the subject experienced a conscious desire to drink was lower in pregnant (287 +/- 1.6 mosmol/kg) compared with postpartum subjects (298 +/- 2.0 mosmol/kg; P less than 0.001). These data demonstrate decreased osmotic thresholds for AVP release and thirst during human pregnancy and explain why gravidas can maintain their new lower Posmol within narrow limits.

Hyperfiltration precedes renal function loss in several nephropathies. Animal studies suggest this may be due to accompanying increases in transglomerular capillary hydrostatic pressure difference (delta P) and/or altered glomerular processing of macromolecules. Renal hemodynamics increase strikingly in human pregnancy. To test the hypothesis that these alterations are not potentially harmful, clearances of inulin, p-aminohippurate, and neutral dextrans were measured at 16- and 36-wk gestation, then 4 mo postpartum, in 11 normotensive women. Results were analyzed using two computer modeling programs. Glomerular filtration rate and renal plasma flow (RPF) were markedly elevated in early and late pregnancy (135 +/- 6 and 895 +/- 53 and 135 +/- 6 and 754 +/- 32 ml/min, respectively, vs. 87 +/- 7 and 520 +/- 17 ml/min postpartum). Gestational hyperfiltration was primarily due to RPF increments with a minor contribution from decrements in capillary oncotic pressure. Fractional dextran clearances (particularly the smaller dextrans, 30-39 A radii) were lower in early pregnancy, decreasing further in late pregnancy. There was no evidence of increased delta P and alterations in glomerular membrane porosity resolved postpartum. These data provide a database by which to study effects of pregnancy on chronic renal disease.

Background: KEAP1 is a ubiquitin ligase adaptor that promotes the ubiquitination and degradation of NRF2, a transcription factor that drives the antioxidant response.Results: Wilms tumor gene on the X chromosome (WTX) stabilizes NRF2 by competing with NRF2 for binding to KEAP1.Conclusion: WTX regulates the antioxidant response.Significance: This study reveals a novel regulatory mechanism governing the antioxidant response.

Summary In nine women studied serially before conception and through the first trimester, plasma osmolality (Posm) started to decline with the first missed menstrual period, was significantly decreased by the fifth week of pregnancy and was 10 mosmol/kg lower than preconception values by the tenth week, changing little thereafter. Changes in plasma sodium (and its attendant anion) accounted for the majority of the decrement. In separate studies, urinary concentration and dilution, assessed by water deprivation and loading, were studied in nine women during their last trimester and again 10–12 weeks post partum. Basal Posm was 9 mosmol/kg lower in the last trimester than post partum (p < 0.001) but the results of concentration and dilution tests were similar during and after pregnancy. Basal urinary arginine vasopressin (AVP) excretion was similar during and after pregnancy and water loading suppressed AVP excretion in both pregnant and postpartum women. An unanticipated observation was that lateral recumbency interfered with urinary concentration tests in both pregnant and postpartum women. The results demonstrate that the decrement in Posm during pregnancy is an early event. The data (urinary AVP excretion, its suppression by water loading and normal concentration and dilution despite a lower plasma tonicity) also suggest that human pregnancy is accompanied by a resetting of the threshold for vasopressin secretion to a lower Posm

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The metabolic clearance rate (MCR) of oxytocin (OT) was determined by use of constant infusion techniques to achieve low and high plasma OT concentrations in 10 women in late pregnancy and again 8-10 wk postpartum (mean plasma oxytocinase activity was 2.1 IU/ml plasma at term and less than 0.1 IU/ml plasma 8-10 wk postpartum). At the lower plasma OT concentrations (5.0 and 5.2 pg/ml, pregnant and postpartum, respectively) produced by infusion of 17.9 ng/min in pregnancy and 4.3 ng/min postpartum, mean MCR of OT was increased fourfold during pregnancy (5.7 +/- 0.6 and 1.3 +/- 0.1 l/min, pregnant and postpartum, respectively; P less than 0.001). At the higher plasma OT concentrations (8.0 and 8.0 pg/ml, pregnant and postpartum, respectively) produced by infusion of 35.7 ng/min in pregnancy and 8.5 ng/min postpartum, mean MCR of OT was likewise markedly increased during pregnancy compared with postpartum values (7.1 +/- 1.9 and 1.4 +/- 0.1 l/min, respectively; P less than 0.01). The MCR of OT was independent of plasma concentration (between 5 and 8 pg/ml) during pregnancy and in the postpartum period. It is concluded that the MCR of OT is increased markedly during human pregnancy. This may be due to concomitant increases in in vivo cystine aminopeptidase activity or other less specific pregnancy-associated metabolic changes.