TY - JOUR
T1 - Acute renal proximal tubule alterations during induced metabolic crises in a mouse model of glutaric aciduria type 1
AU - Thies, Bastian
AU - Meyer-Schwesinger, Catherine
AU - Lamp, Jessica
AU - Schweizer, Michaela
AU - Koeller, David M.
AU - Ullrich, Kurt
AU - Braulke, Thomas
AU - Mühlhausen, Chris
N1 - Funding Information:
This work was supported by Deutsche Forschungsgemeinschaft , grants MU 1778/2-1 and MU 1778/2-2 (to C.M. and J.L.). We thank Chudamani Raithore for excellent technical assistance with electron microscopy.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Acute tubular injury
KW - Dicarboxylate transporter
KW - Glutaric aciduria type 1
KW - Metabolic disease
KW - Transporter expression
UR - http://www.scopus.com/inward/record.url?scp=84879383463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879383463&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2013.04.019
DO - 10.1016/j.bbadis.2013.04.019
M3 - Article
C2 - 23623985
AN - SCOPUS:84879383463
SN - 0925-4439
VL - 1832
SP - 1463
EP - 1472
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 10
ER -