Prouroguanylin’s role in the homeostatic response to dietary sodium: hormone precursor or active signaling agent?

High blood pressure affects more than 70 million Americans, putting them at a much greater risk for heart disease or a stroke. Sodium (Na+) is a major determinant of blood osmolarity and volume, and therefore plays a critical role in blood pressure regulation. Prouroguanylin (proUgn) has been implicated as a signal being sent from the small intestine to the kidney, in response to oral Na+ intake, that intestinal Na+ adsorption is eminent and renal Na+ excretion is necessary to maintain homeostasis. This concept, known as post-prandial natriuresis, is based on past observations of a faster natriuretic response from an oral salt load than from an equimolar intravenous infusion of NaCl. This role for proUgn is contentious however, as it has not been clearly shown if the role played by proUgn is that of a primary messenger from the intestine to the kidney in response to salt, if it is a intrarenal paracrine mechanism secondary to some other extrarenal signal in response to oral Na+ or even if it is proUgn itself or one of its' metabolites that are acting in the kidney. My studies address identification and quantification of proUgn and Ugn in relevant tissue compartments and additionally, I look at the effects of dietary Na+ on changes in the expression of proUgn and Ugn in these tissues. A novel adaptation of a binding assay technique allowed for urinary Ugn measurements that were found to directly correlate with dietary Na+ intake on a time scale that the prior techniques were insufficiently sensitive to achieve. Enteric and plasma proUgn do not change in response to dietary Na+, however a renal proUgn expression and Ugn in the urine do. Changes in plasma proUgn elicit a greater natriuretic response with a lower urinary Ugn concentration than urinary Ugn concentrations from infusions of Ugn in the blood. My conclusion is that proUgn is a secondary agent involved in volume and Na+ homeostasis, acting though some as yet unidentified renal metabolite/receptor mechanism. Further studies should focus on if there is another active cleavage product of proUgn and what receptor it (proUgn or Ugn) acts through

Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor

Asthma is a chronic airway disease characterized by inflammation, mucus hypersecretion and abnormal airway smooth muscle (ASM) contraction. Bacterial permeability family member A1, BPIFA1, is a secreted innate defence protein. Here we show that BPIFA1 levels are reduced in sputum samples from asthmatic patients and that BPIFA1 is secreted basolaterally from healthy, but not asthmatic human bronchial epithelial cultures (HBECs), where it suppresses ASM contractility by binding to and inhibiting the Ca2+ influx channel Orai1. We have localized this effect to a specific, C-terminal α-helical region of BPIFA1. Furthermore, tracheas from Bpifa1−/− mice are hypercontractile, and this phenotype is reversed by the addition of recombinant BPIFA1. Our data suggest that BPIFA1 deficiency in asthmatic airways promotes Orai1 hyperactivity, increased ASM contraction and airway hyperresponsiveness. Strategies that target Orai1 or the BPIFA1 deficiency in asthma may lead to novel therapies to treat this disease

Diet-Induced and Age-Related Changes in the Quadriceps Muscle: MRI and MRS in a Rat Model of Sarcopenia

Background: Knowledge about the molecular pathomechanisms of sarcopenia is still sparse, especially with regard to nutritional risk factors and the subtype of sarcopenic obesity. Objective: The aim of this study was to characterize diet-induced and age-related changes on the quality and quantity of the quadriceps muscle in a rat model of sarcopenia by different magnetic resonance (MR) techniques. Methods: A total of 36 6-month-old male Sprague-Dawley rats were randomly subdivided into 2 groups and received either a high-fat diet (HFD) or a control diet (CD). At the age of 16 months, 15 HFD and 18 CD rats underwent MR at 1.5 T. T1-weighted images as well as T2 relaxation time maps were acquired perpendicular to the long axis of the quadriceps muscles. Maximum cross-sectional area (CSA) of the quadriceps muscle was measured on T1-weighted images, and T2 relaxation times of muscle were assessed in a region without visible intramuscular fat (T2lean muscle) and across the complete CSA (T2muscle). Furthermore, 1H-MR spectroscopy was performed to evaluate the relative lipid content of the quadriceps muscles. These measurements were repeated 5 months later in the surviving 8 HFD and 14 CD rats. Results: HFD rats revealed significantly decreased CSA and CSA per body weight (BW) as well as prolonged T2 relaxation times of muscle. A higher weight gain (upper tertile during the first 6 months of diet in CD rats) resulted in a significant change of T2muscle, but had no relevant impact on CSA. Advancing age up to 21 months led to significantly decreased BW, CSA and CSA/BW, significantly prolonged T2muscle and T2lean muscle and enlarged lipid content in the quadriceps muscle. Conclusions: In an experimental setting a chronically fat-enriched diet was shown to have a relevant and age-associated influence on both muscle quantity and quality. By translational means the employed MR techniques give rise to the possibility of an early detection and noninvasive quantification of sarcopenia in humans, which is highly relevant for the field of geriatrics

The Peptidyl Prolyl Isomerase Rrd1 Regulates the Elongation of RNA Polymerase II during Transcriptional Stresses

Rapamycin is an anticancer agent and immunosuppressant that acts by inhibiting the TOR signaling pathway. In yeast, rapamycin mediates a profound transcriptional response for which the RRD1 gene is required. To further investigate this connection, we performed genome-wide location analysis of RNA polymerase II (RNAPII) and Rrd1 in response to rapamycin and found that Rrd1 colocalizes with RNAPII on actively transcribed genes and that both are recruited to rapamycin responsive genes. Strikingly, when Rrd1 is lacking, RNAPII remains inappropriately associated to ribosomal genes and fails to be recruited to rapamycin responsive genes. This occurs independently of TATA box binding protein recruitment but involves the modulation of the phosphorylation status of RNAPII CTD by Rrd1. Further, we demonstrate that Rrd1 is also involved in various other transcriptional stress responses besides rapamycin. We propose that Rrd1 is a novel transcription elongation factor that fine-tunes the transcriptional stress response of RNAPII