Aristolochic acid-induced nephropathy is attenuated in mice lacking the neutral amino acid transporter B0AT1 (Slc6a19)

Abstract

B0AT1 (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 B0AT1 in the nephropathy induced by aristolochic acid (AA), which targets the proximal tubule, littermate female B0AT1-deficient (Slc6a19-/-), heterozygote (Slc6a19+/-) and wild-type (WT) mice were administered AA (10 mg/kg i.p.) or vehicle every 3 days for 3 weeks and analyses performed after the last injection or 3 weeks later. Vehicle-treated mice lacking Slc6a19 showed normal body and kidney weight and plasma creatinine vs. WT. Urinary glucose/creatinine ratio and urinary albumin/creatinine ratio (UACR) were 2-4 times higher in vehicle-treated Slc6a19-/- vs. WT mice, associated with lesser expression of early proximal transporters SGLT2 and megalin, respectively. AA caused tubular injury independently of B0AT1, including robust increases in cortical mRNA expression of p53, p21 and Havcr1, downregulation of related proximal tubule amino acid transporters B0AT2 (Slc6a15), B0AT3 (Slc6a18) and Slc7a9, and modest histological tubular damage and rise in plasma creatinine. Absence of B0AT1, however, attenuated AA-induced cortical upregulation of mRNA markers of senescence (p16), inflammation (Lcn2, Ccl2, Ccr2), and fibrosis (Timp1, Tgfb1, Col1a1), associated with lesser fibrosis staining, lesser suppression of proximal tubular organic anion transporter OAT1, restoration of SGLT2 expression, and prevention of the AA-induced 5-fold increase in UACR observed in WT. The data suggest that proximal tubular B0AT1 is important for the physiology of renal glucose and albumin retention but potentially deleterious for the kidney response following AA-induced kidney injury.