Abstract: PO1250
Peroxisomes Are Dispensable for Normal Renal Function
Session Information
- Cystic Kidney Disease - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Bignon, Yohan, Universite de Lausanne Faculte de biologie et medecine, Lausanne, VD, Switzerland
- Ansermet, Camille, Universite de Lausanne Faculte de biologie et medecine, Lausanne, VD, Switzerland
- Centeno, Gabriel, Universite de Lausanne Faculte de biologie et medecine, Lausanne, VD, Switzerland
- Garcia, Andy, Universite de Lausanne Faculte de biologie et medecine, Lausanne, VD, Switzerland
- Pradervand, Sylvain, Genomic Technologies Facility, University of Lausanne, Lausanne, Vaud, Switzerland
- Firsov, Dmitri, Universite de Lausanne Faculte de biologie et medecine, Lausanne, VD, Switzerland
Background
Peroxisomes are single membrane-bound cellular organelles identified in the kidney in 1954. Peroxisomes are ubiquitously present in eucaryotic cells with highest abundance in renal proximal tubule cells and hepatocytes. The variety of metabolic and antioxidant functions in which peroxisomes are involved is highlighted by human mutations in PEX genes encoding peroxins proteins required for proper peroxisome biogenesis. Hence, the complete loss of peroxisomes causes Zellweger’s spectrum disorders (ZSD), devastating multiorgan failure which include renal impairment. However, the (patho)physiological role of peroxisomes in the kidney remains unknown.
Methods
Here we addressed the role of peroxisomes in renal function in male and female adult or infant mice with conditional ablation of Pex5-driven peroxisomal biogenesis in the renal tubule (cKO mice).
Results
Functional and histological analyses of both infant and adult cKO mice did not reveal any overt kidney phenotype. However, male cKO mice exhibited substantial reduction in kidney weight to body weight ratio. Stereological analysis of electronic microscopy results showed a complete absence of peroxisomes accompanied by increase in the number and in the volume of mitochondria in proximal tubule cells of cKO mice. Integrated deep transcriptome-sequencing and metabolome analyses revealed profound reprogramming of a great number of metabolic pathways, including biosynthesis of different classes of lipids such as plasmalogens and sphingomyelins (two major classes of membrane lipids) and the metabolism of glutathione. Although this analysis suggested compensated oxidative stress, four weeks of high fat feeding challenging the ability of proximal tubule cells to metabolize lipids did not induce significant renal impairments in cKO mice.
Conclusion
We demonstrate that renal tubular peroxisomes are dispensable for normal renal function. This indicates a large flexibility of proximal tubule cells both in terms of lipid membrane composition and metabolic/antioxidant functions. Our data also suggest that renal impairments in ZSD patients are of extrarenal origin.
Funding
- Government Support – Non-U.S.