Transcriptomic analysis and plasma metabolomics in Aldh16a1-null mice reveals a potential role of ALDH16A1 in renal function

Abstract ALDH16A1 is a novel member of the ALDH superfamily that is enzymatically-inactive and highly expressed in the kidney. Recent studies identified an association between a rare missense single nucleotide variant (SNV) in the ALDH16A1 gene and elevated serum uric acidlevels and gout. The present study explores the mechanisms by which ALDH16A1 influences uric acidhomeostasis in the kidney. We generated and validated a mouse line with global disruption of the Aldh16a1 gene through gene targetingand performed RNA-seqanalyses in the kidney of wild-type (WT) and Aldh16a1 knockout (KO) mice, along with plasma metabolomics. We found that ALDH16A1 is expressed in proximal and distal convoluted tubulecells in the cortex of the kidney and in zone 3 hepatocytes. RNA-seqand gene ontology enrichment analyses showed that cellular lipid and lipid metabolic processes are up-regulated. Three transporters localized in the apical membrane of the proximal convoluted tubuleof the kidney known to influence urate/ uric acidhomeostasis were found to be up-regulated ( Abcc4, Slc16a9 ) or down-regulated ( Slc17a3). An initial metabolomicsanalysis in plasma revealed an altered lipid profile in KO mice that is in agreement with our RNA-seqanalysis. This is the first study demonstrating a functional role of ALDH16A1 in the kidney.