A knock-in rat model unravels acute and chronic renal toxicity in glutaric aciduria type I.

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State: Public
Version: author
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_05A57A99C9CF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A knock-in rat model unravels acute and chronic renal toxicity in glutaric aciduria type I.
Journal
Molecular genetics and metabolism
Author(s)
Gonzalez Melo M., Fontana A.O., Viertl D., Allenbach G., Prior J.O., Rotman S., Feichtinger R.G., Mayr J.A., Costanzo M., Caterino M., Ruoppolo M., Braissant O., Barbey F., Ballhausen D.
ISSN
1096-7206 (Electronic)
ISSN-L
1096-7192
Publication state
Published
Issued date
10/11/2021
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
Glutaric aciduria type I (GA-I, OMIM # 231670) is an autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). The principal clinical manifestation in GA-I patients is striatal injury most often triggered by catabolic stress. Early diagnosis by newborn screening programs improved survival and reduced striatal damage in GA-I patients. However, the clinical phenotype is still evolving in the aging patient population. Evaluation of long-term outcome in GA-I patients recently identified glomerular filtration rate (GFR) decline with increasing age. We recently created the first knock-in rat model for GA-I harboring the mutation p.R411W (c.1231 C>T), corresponding to the most frequent GCDH human mutation p.R402W. In this study, we evaluated the effect of an acute metabolic stress in form of high lysine diet (HLD) on young Gcdh <sup>ki/ki</sup> rats. We further studied the chronic effect of GCDH deficiency on kidney function in a longitudinal study on a cohort of Gcdh <sup>ki/ki</sup> rats by repetitive <sup>68</sup> Ga-EDTA positron emission tomography (PET) renography, biochemical and histological analyses. In young Gcdh <sup>ki/ki</sup> rats exposed to HLD, we observed a GFR decline and biochemical signs of a tubulopathy. Histological analyses revealed lipophilic vacuoles, thinning of apical brush border membranes and increased numbers of mitochondria in proximal tubular (PT) cells. HLD also altered OXPHOS activities and proteome in kidneys of Gcdh <sup>ki/ki</sup> rats. In the longitudinal cohort, we showed a progressive GFR decline in Gcdh <sup>ki/ki</sup> rats starting at young adult age and a decline of renal clearance. Histopathological analyses in aged Gcdh <sup>ki/ki</sup> rats revealed tubular dilatation, protein accumulation in PT cells and mononuclear infiltrations. These observations confirm that GA-I leads to acute and chronic renal damage. This raises questions on indication for follow-up on kidney function in GA-I patients and possible therapeutic interventions to avoid renal damage.
Keywords
(68)Ga EDTA, Glutaric aciduria type I, Organic acidurias, Renal toxicity, Tubulopathy
Pubmed
Open Access
Yes
Create date
22/11/2021 7:56
Last modification date
26/11/2021 17:38
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