Aristolochic acid-induced nephropathy is attenuated in mice lacking the neutral amino acid transporter BAT1 ().

BAT1 (Slc6a19) mediates absorption of neutral amino acids in the small intestine and in the kidneys, where it is primarily expressed in early proximal tubules (S1-S2). To determine the role of BAT1 in nephropathy induced by aristolochic acid (AA), which targets the proximal tubule, littermate female BAT1-deficient (), heterozygous (), and wild-type (WT) mice were administered AA (10 mg/kg ip) or vehicle every 3 days for 3 wk, and analyses were performed after the last injection or 3 wk later. Vehicle-treated mice lacking showed normal body and kidney weight and plasma creatinine versus WT mice. The urinary glucose-to-creatinine ratio (UGCR) and urinary albumin-to-creatinine ratio (UACR) were two to four times higher in vehicle-treated versus WT mice, associated with lesser expression of early proximal transporters Na-glucose cotransporter 2 and megalin, respectively. AA caused tubular injury independently of BAT1, including robust increases in cortical mRNA expression of , , and hepatitis A virus cellular receptor 1 (), downregulation of related proximal tubule amino acid transporters BAT2 (), BAT3 (), and , and modest histological tubular damage and a rise in plasma creatinine. Absence of BAT1, however, attenuated AA-induced cortical upregulation of mRNA markers of senescence (), inflammation [lipocalin 2 (), C-C motif chemokine ligand 2 (), and C-C motif chemokine receptor 2 ()], and fibrosis [tissue inhibitor of metallopeptidase 1 (), transforming growth factor-β1 (), and collagen type I-α ()], associated with lesser fibrosis staining, lesser suppression of proximal tubular organic anion transporter 1, restoration of Na-glucose cotransporter 2 expression, and prevention of the AA-induced fivefold increase in the urinary albumin-to-creatinine ratio observed in WT mice. The data suggest that proximal tubular BAT1 is important for the physiology of renal glucose and albumin retention but potentially deleterious for the kidney response following AA-induced kidney injury. Based on insights from studies manipulating glucose transport, the hypothesis has been proposed that inhibiting intestinal uptake or renal reabsorption of energy substrates has unique therapeutic potential to improve metabolic disease and kidney outcome in response to injury. The present study takes this idea to BAT1, the major transporter for neutral amino acids in the intestine and kidney, and shows that its absence attenuates aristolochic acid-induced nephropathy.