title: Acute renal proximal tubule alterations during induced metabolic crises in a mouse model of glutaric aciduria type 1.
abstract: The metabolic disorder glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of the pathologic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in blood, urine and tissues. Affected patients are prone to metabolic crises developing during catabolic conditions, with an irreversible destruction of striatal neurons and a subsequent dystonic-dyskinetic movement disorder. The pathogenetic mechanisms mediated by GA and 3OHGA have not been fully characterized. Recently, we have shown that GA and 3OHGA are translocated through membranes via sodium-dependent dicarboxylate cotransporter (NaC) 3, and organic anion transporters (OATs) 1 and 4. Here, we show that induced metabolic crises in Gcdh(-/-) mice lead to an altered renal expression pattern of NaC3 and OATs, and the subsequent intracellular GA and 3OHGA accumulation. Furthermore, OAT1 transporters are mislocalized to the apical membrane during metabolic crises accompanied by a pronounced thinning of proximal tubule brush border membranes. Moreover, mitochondrial swelling and increased excretion of low molecular weight proteins indicate functional tubulopathy. As the data clearly demonstrate renal proximal tubule alterations in this GA1 mouse model during induced metabolic crises, we propose careful evaluation of renal function in GA1 patients, particularly during acute crises. Further studies are needed to investigate if these findings can be confirmed in humans, especially in the long-term outcome of affected patients.
authors.affiliation: Department of Biochemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Thies
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.forename: Jessica
authors.initials: J
authors.lastname: Lamp
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000473:pathology*; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000473:pathology*; D004195:Disease Models, Animal; D005977:Glutarates / Q000378:metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal
chemical_list: D005977:Glutarates; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid
keywords: 3-hydroxyglutaric acid; 3OHGA; Acute tubular injury; Dicarboxylate transporter; GA; GA1; GABA; GCDH; Glutaric aciduria type 1; HNF; HPD; MUP1; Metabolic disease; N-methyl-d-aspartate; ND; NHERF; NMDA; NaC; OAT; OATP; PAS; RST; SLC; Transporter expression; WGA; WT; glutaric acid; glutaric aciduria type 1; glutaryl-CoA dehydrogenase; hepatocyte nuclear factor; high protein diet; major urinary protein 1; normal diet; organic anion transporter; organic anion transporting polypeptide; periodic acid-Schiff; renal-specific transporter; sodium hydrogen exchanger regulatory factor; sodium-dependent dicarboxylate cotransporter; solute carrier; wheat germ agglutinin; wild-type; γ-aminobutyric acid