Mitochondrial and NAD+ metabolism predict recovery from acute kidney injury in a diverse mouse population

Author list

Jean-David Morel (1), Maroun Bou Sleiman (1), Terytty Yang Li (1), Giacomo von Alvensleben (1), Alexis M. Bachmann (1), Dina Hofer (1), Ellen Broeckx (2), Jing Ying Ma (2), Vinicius Carreira (2), Tao Chen (2), Nabil Azhar (2), Romer A. Gonzalez-Villalobos (2), Matthew Breyer (2), Dermot Reilly (2), Shannon Mullican (2), and Johan Auwerx (1)

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.

Overview:

The aim of this app is to provide an easy access to the available data and results. The 3 main panels (Metadata, Phenotype explorer, Expression console) allow to respectively explore the metadata, the measured phenotypes and the genetic expression levels and correlation with the phenotypes.

Experimental design:

This study used male animals from 7 domesticated (C57BL/6J, DBA/2J, A/J, 129S1/SvlmJ,WSB/EiJ) or wild-derived (CAST/EiJ, PWK/PhJ) inbred mouse strains drawn from founders the well-characterized BXD and collaborative cross panels, that are well known for their diversity in genetics, as well as in molecular and cardio-metabolic phenotypes. The CC founder strains NOD/ShiLtJ and NZO/HlLtJ were excluded because they naturally develop diabetes and other symptoms in the absence of injury (NOD: diabetes and immune defects, NZO: severe obesity and diabetes) which causes hyperfiltration and could interfere with the conclusions of the study.

Ethical approval of animal studies

All research was approved by the Swiss cantonal veterinary authorities of Vaud under license VD3418.

Included measurements:

In-life phenotyping:

Body weight, food intake, organ weights

Urine biochemistry:

Creatinine, Albumin

Plasma biochemistry:

Creatinine, BUN

Plasma circulating factors:

GDF-15, FGF-21, TIMP-1

Kidney RNAseq:

210 Kidneys at 2 control timepoints (Week 1, 6) and three folic-acid injured timepoints (Week 1, 2 and 6)

Acknowledgements:

We thank Laure Vogeleisen, Marie Janod, Sabrina Bichet, Thibaud Clerc, Jéromine Imbach (EPFL), the SV animal facility (UDP), and the Schoonjans’ and Auwerx’s lab members for technical assistance and discussions. This work was supported by the École Polytechnique Fédérale de Lausanne (EPFL), funding provided by Janssen Research and Development, LLC and grants from the European Research Council (ERC-AdG-787702), and the Swiss National Science Foundation (SNSF 31003A-179435 and Sinergia CRSII5_202302).

Declaration of Interests:

This work was, in part, funded through a grant from Janssen Research and Development. JA is a founder and/or consultant to MitoBridge/Astellas, Metro Biotech, Amazentis, and NOV Metapharma. JYM, VC, TC, SM, MB, DR, and RAGV are Janssen Research and Development LLC employees and/or Johnson and Johnson stock holders.

Author contributions:

JDM, MBS, SM, MB, DR, RAGV, and JA conceived and designed the project. DH performed animal experiments together with technicians and animal facility personnel. TYL and JDM performed laboratory experiments. EB prepared histology samples, JYM and VC performed PSR quantitation, and TC completed histopathology analysis. JDM, MBS, AMB, and NA analyzed the data. MBS and GVA created the web interface. JDM and JA wrote the manuscript with input from all the authors.

Author affiliations:

Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Janssen Research and Development LLC.