ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2023 and some content may be unavailable. To unlock all content for 2023, please visit the archives.

Abstract: FR-PO1007

Glucagon Agonism Protects the Kidney from Obesity by Restoring Peroxisomal Catalase and Fatty Acid Oxidation Capacity

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Lindsay, Ross T., AstraZeneca R&D Cambridge, Cambridge, United Kingdom
  • Laker, Rhianna C., AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, United States
  • Gill, Benji Manov, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, United States
  • Yan, Zhen, Virginia Polytechnic Institute and State University, Roanoke, Virginia, United States
  • Larsen, Martin Roessel, Syddansk Universitet, Odense, Syddanmark, Denmark
  • Rhodes, Christopher J., AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, United States

Obesity challenges the nephron through fatty acid overload, leading to impaired energy metabolism and impaired renal filtration. Glucagon agonism elicits well described enhancement of fatty acid oxidation and mitochondrial rejuvenation in the liver and other organs, and was hypothesised here to protect the kidney from obesity-related pathology.


Sprague Dawley rats fed HFHS (DIO) or chow diet for 10 weeks were administered 10nmol/kg lipidated glucagon receptor agonist g1437 daily for seven days. IF was used to visualise the distribution and morphology of peroxisomes and mitochondria across the kidney, alongside the organelle content of key metabolic and ROS handling enzymes. Primary human PTECs transfected with either MitoTimer or with a novel peroxisomal ROS sensor were cultured with and without linoleic/oleic acid for 72 hours alongside 100 nM g1437 or vehicle. To interrogate the underlying signalling mechanism of glucagon, cortex and medulla from mice acutely administered 10nmol/kg g1437 were analysed by phosphoproteomics.


Kidneys of DIO rats demonstrated peroxisomal proliferation and altered mitochondrial morphology. Glucagon agonism also induced mitochondrial and peroxisomal morphological changes. Peroxisomal catalase and FAO enzyme content was perturbed in kidneys of DIO relative to chow fed rats. Concomitantly with weight loss, renal peroxisomal and mitochondrial FAO enzyme content was partially restored in g1437 administered rats. Primary human PTECs cultured with 150 µM linoleic/oleic acid mixture for 72 hours demonstrated greater mitochondrial and peroxisomal reactive oxygen species generation than controls. Phosphoproteomics determined that catalase was 1.48-fold more phosphorylated in kidney cortex of mice acutely administered g1437, a phosphorylation shown to enhance catalase activity. Peroxisomal fatty acid oxidation biogenesis were pathways significantly phosphorylated as part of the glucagon signalling cascade.


Obesity and fatty acid overload led to fission of renal mitochondria and peroxisomes, alongside increased capacity for ROS production and FAO. Glucagon agonism did not reverse changes in organelle morphology, yet enhanced FAO capacity and lowered ROS production capacity, possibly through catalase phosphorylation.


  • Commercial Support – AstraZeneca