Faculty Collaboration Database

Exploration of cardiometabolic and developmental significance of angiotensinogen expression by cells expressing the leptin receptor or agouti-related peptide. Am J Physiol Regul Integr Comp Physiol 2020 May 01;318(5):R855-R869

Date

03/19/2020

Pubmed ID

32186897

Pubmed Central ID

PMC7272763

DOI

10.1152/ajpregu.00297.2019

Scopus ID

2-s2.0-85083546405 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Angiotensin II (ANG II) Agtr1a receptor (AT_1A) 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 AT_1A signaling 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 (Agt^Lepr-KO and Agt^Agrp-KO mice, respectively). Agt^Lepr-KO mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, Agt^Agrp-KO mice 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 Agt^Agrp-KO mice 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.

Author List

Sapouckey SA, Morselli LL, Deng G, Patil CN, Balapattabi K, Oliveira V, Claflin KE, Gomez J, Pearson NA, Potthoff MJ, Gibson-Corley KN, Sigmund CD, Grobe JL

Authors

Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
Lisa Morselli MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Chetan N. Patil Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adrenal Glands
Agouti-Related Protein
Angiotensinogen
Animals
Arcuate Nucleus of Hypothalamus
Autocrine Communication
Energy Metabolism
Female
Gene Expression Regulation, Developmental
Kidney
Male
Mice, Knockout
Myocardium
Paracrine Communication
Receptors, Leptin
Serum Albumin
Signal Transduction