肝臓と腎臓の疾患をモデル化する(Modeling liver and kidney disease)

2023-02-21 スイス連邦工科大学ローザンヌ校(EPFL)

<関連情報>

• https://actu.epfl.ch/news/modeling-liver-and-kidney-disease/
• https://rupress.org/jem/article/220/4/e20221738/213867/The-genetic-background-shapes-the-susceptibility
• https://insight.jci.org/articles/view/164626

ミトコンドリア機能障害とNASHの進行のしやすさを形成する遺伝的背景 The genetic background shapes the susceptibility to mitochondrial dysfunction and NASH progression

Giorgia Benegiamo,Giacomo V.G. von Alvensleben,Sandra Rodríguez-López,Ludger J.E. Goeminne,Alexis M. Bachmann,Jean-David Morel,Ellen Broeckx,Jing Ying Ma,Vinicius Carreira,Sameh A. Youssef,Nabil Azhar,Dermot F. Reilly,Katharine D’Aquino,Shannon Mullican,Maroun Bou-Sleiman,Johan Auwerx
Journal of Experimental Medicine  Published:February 14 2023
DOI:https://doi.org/10.1084/jem.20221738

Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene–environment interactions. We tested the susceptibility of seven mouse strains to develop NASH. The severity of the clinical phenotypes observed varied widely across strains. PWK/PhJ mice were the most prone to develop hepatic inflammation and the only strain to progress to NASH with extensive fibrosis, while CAST/EiJ mice were completely resistant. Levels of mitochondrial transcripts and proteins as well as mitochondrial function were robustly reduced specifically in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, the NASH gene expression profile of PWK/PhJ mice had the highest overlap with the human NASH signature. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model with features of the human NASH.

ミトコンドリアとNAD+代謝が、多様なマウス集団における急性腎不全からの回復を予測する Mitochondrial and NAD+ metabolism predict recovery from acute kidney injury in a diverse mouse population

Jean-David Morel, Maroun Bou Sleiman, Terytty Yang Li, Giacomo von Alvensleben, Alexis M. Bachmann, Dina Hofer, Ellen Broeckx, Jing Ying Ma, Vinicius Carreira, Tao Chen, Nabil Azhar, Romer A. Gonzalez-Villalobos, Matthew Breyer, Dermot Reilly, Shannon Mullican and Johan Auwerx
Journal of Clinical Investigation  Published February 8, 2023
DOI:https://doi.org/10.1172/jci.insight.164626

Abstract

Acute kidney failure and chronic kidney disease are global health issues steadily rising in incidence and prevalence. Animal models on a single genetic background have so far failed to recapitulate the clinical presentation of human nephropathies. Here, we used a simple model of folic acid–induced kidney injury in 7 highly diverse mouse strains. We measured plasma and urine parameters, as well as renal histopathology and mRNA expression data, at 1, 2, and 6 weeks after injury, covering the early recovery and long-term remission. We observed an extensive strain-specific response ranging from complete resistance of the CAST/EiJ to high sensitivity of the C57BL/6J, DBA/2J, and PWK/PhJ strains. In susceptible strains, the severe early kidney injury was accompanied by the induction of mitochondrial stress response (MSR) genes and the attenuation of NAD⁺ synthesis pathways. This is associated with delayed healing and a prolonged inflammatory and adaptive immune response 6 weeks after insult, heralding a transition to chronic kidney disease. Through a thorough comparison of the transcriptomic response in mouse and human disease, we show that critical metabolic gene alterations were shared across species, and we highlight the PWK/PhJ strain as an emergent model of transition from acute kidney injury to chronic disease.