Search

Generalized cellular ‘stress’ (i.e., oxidative, mitochondrial) within the syncytiotrophoblast (STB) layer of placenta is theorized to drive the pathogenesis of preeclampsia (PE), but the causes and consequences of this stress have yet to be clearly elucidated. Many hormones implicated in the disorder signal through the Gq pathway and have been associated with placental oxidative damage and maternal symptoms. Here, we provide novel evidence of elevated Gq stimulation (n=8-10 normalized area PLCB protein, control 1340±370, PE 3350±750, P=0.04) and an antioxidant response (n=8 normalized area SOD2 protein, control 3020±1160, PE 6700±1250, P=0.04) within STB cells of PE placenta. Thus, we hypothesized excess STB-specific Gq signaling would be sufficient to cause phenotypes of PE and that administration of a mitochondrial-targeted antioxidant (mitoquinone) would mitigate these effects. Activation of the Gq cascade in STB cells was achieved by crossing dams harboring a Cre-dependent Gq-coupled DREADD (hM3Dq) with Gcm1-Cre+/- sires and injecting clozapine N-oxide (CNO) or saline mid-gestation (GD12.5-14.5) before tissue collection at GD14.5. Gq stimulation increased mean arterial pressure (n=6-8, CNO 115±2mmHg, saline 110±2mmHg, GD 13-16.5, P=0.04), exacerbated urine protein excretion (n=9-11 CNO 43±4mg/d, saline 28±3mg/day, P=0.001), and elevated circulating pro-inflammatory factors (MCP5, LIX, TIMP1, MIP3B, GCSF, IL12p40, MDC, P NIH: HL134850, HL084207, DK133121, HL150340; AHA: 826132, 18EIA33890055 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Angiotensin II (ANG II) Agtr1a receptor (AT1A) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor ( Lepr) and agouti-related peptide ( Agrp). Agtr1a expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT1Asignaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen ( Agt, encoding AGT) with mice expressing Cre-recombinase via the Lepr or Agrp promoters to cause cell-specific deletions of Agt ( AgtLepr-KOand AgtAgrp-KOmice, respectively). AgtLepr-KOmice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, AgtAgrp-KOmice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body Agt deficiency or Agt disruption in albumin ( Alb)-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult AgtAgrp-KOmice exhibited normal circulating AGT protein and hepatic Agt mRNA expression but reduced Agt mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that Agrp and Alb are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both Agrp-Cre and Alb-Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of Agt is critically required for normal renal development and survival.

Angiotensin II (ANG) stimulates the release of arginine vasopressin (AVP) from the neurohypophysis through activation of the AT1receptor within the brain, although it remains unclear whether AT1receptors expressed on AVP-expressing neurons directly mediate this control. We explored the hypothesis that ANG acts through AT1Areceptors expressed directly on AVP-producing cells to regulate AVP secretion. In situ hybridization and transgenic mice demonstrated localization of AVP and AT1AmRNA in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN), but coexpression of both AVP and AT1AmRNA was only observed in the SON. Mice harboring a conditional allele for the gene encoding the AT1Areceptor (AT1Aflox) were then crossed with AVP-Cre mice to generate mice that lack AT1Ain all cells that express the AVP gene (AT1AAVP-KO). AT1AAVP-KOmice exhibited spontaneously increased plasma and serum osmolality but no changes in fluid or salt-intake behaviors, hematocrit, or total body water. AT1AAVP-KOmice exhibited reduced AVP secretion (estimated by measurement of copeptin) in response to osmotic stimuli such as acute hypertonic saline loading and in response to chronic intracerebroventricular ANG infusion. However, the effects of these receptors on AVP release were masked by complex stimuli such as overnight dehydration and DOCA-salt treatment, which simultaneously induce osmotic, volemic, and pressor stresses. Collectively, these data support the expression of AT1Ain AVP-producing cells of the SON but not the PVN, and a role for AT1Areceptors in these cells in the osmotic regulation of AVP secretion.

Multiple organ systems, including the gastrointestinal tract, pancreas, and hepatobiliary systems, are affected by cystic fibrosis (CF). Many of these changes begin early in life and are difficult to study in young CF patients. Recent development of novel CF animal models has expanded opportunities in the field to better understand CF pathogenesis and evaluate traditional and innovative therapeutics. In this review, we discuss manifestations of CF disease in gastrointestinal, pancreatic, and hepatobiliary systems of humans and animal models. We also compare the similarities and limitations of animal models and discuss future directions for modeling CF.

Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5–7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a “tissue rejection” type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein by-product of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Furthermore, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal, and vascular systems in the nonpregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established midpregnancy dysfunctions that cause preeclampsia.