Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease

Abstract

Metabolic reprogramming is a hallmark of diabetic kidney disease (DKD); nutrient overload leads to increased production of metabolic byproducts that may become toxic at high levels. One metabolic byproduct may be 2-hydroxyglutarate (2-HG), a metabolite with many regulatory functions that exists in both enantiomeric forms physiologically. We quantitatively determined the levels of L and D-2HG enantiomers in the urine, plasma, and kidney cortex of db/db mice, a pathophysiologically relevant murine model of type 2 diabetes and DKD. We found increased fractional excretion of both L and D-2HG enantiomers, suggesting increased tubular secretion and/or production of the two metabolites in DKD. Quantitation of TCA cycle metabolites in db/db cortex suggests that TCA cycle overload and an increase in 2-HG precursor substrate, α-ketoglutarate, drive the increased L and D-2HG production in DKD. In conclusion, we demonstrated increased 2-HG enantiomer production and urinary excretion in murine type 2 DKD, which may contribute to metabolic reprogramming and progression of diabetic kidney disease.