Disruption of Slc7a9 transporter impairs amino acid homeostasis and contributes to kidney injury in Dahl SS rats

Amino acids (AA) play a significant role in the pathophysiology of hypertension and kidney injury. Our previous studies suggest that supplementation of specific AAs, such as lysine, can mitigate hypertension and protect the kidneys, likely through inhibiting tubular albumin reabsorption. Lysine supplementation potentially enhances kidney function by removing harmful metabolites and boosting beneficial ones. Therefore, we hypothesized that disruption in lysine transport would impair AA homeostasis, subsequently affecting blood pressure and kidney function. In kidneys, b(0,+)-type amino acid transporter 1 (b(0,+)AT1) ( Slc7a9 ) is responsible for transporting dibasic AAs, including lysine. GWAS studies highlighted the role of SLC7A9 in kidney disease. We used CRISPR/Cas9 to create a Slc7a9 -/- rat model on the Dahl SS background to test the hypothesis. Disruption of the b(0,+)AT1transporter in Dahl SS rats results in various physiological and metabolic changes, including reduced body weight, hepatic steatosis, decreased diuresis, and alterations in urine sediment composition (hexagonal and needle-shaped crystals), suggesting potential kidney damage. Slc7a9 -/- rats demonstrated significant aminoaciduria, particularly increased fractional excretion of arginine (0.25 ± 0.1 & 76 ± 18 %, p <0.003), lysine (0.13 ± 0.03 & 39 ± 9 %, p <0.003), methylhistidine (1.3 ± 0.5 & 36 ± 9 %, p <0.003) and ornithine (0.1 ± 0.04 & 21 ± 5 %, p <0.002). Male SS Slc7a9-/- animals showed higher levels of albuminuria (Alb/Cre: 1.6 ± 0.2 & 2.5 ± 0.6) and altered responses to lysine supplementation (“lysine test”). Proteomic and metabolomic analyses indicate widespread changes in protein expression and metabolite levels across different organs and fluids, particularly affecting pathways related to the TCA cycle and glycolysis/gluconeogenesis. We observed higher levels of malate, citrate, cis-aconitate, glutaric, and acetoacetic acids in urine, alongside a decrease in malate levels in the heart. Single nucleus RNA-Seq and pathway analysis highlighted differential regulation of metabolic pathways, including reduced glutathione metabolism (downregulated Gpx3, Gsta1, Gsta2 in multiple cell clusters) and increased oxidative stress in Slc7a9 -/- rats. Therefore, this study highlights the critical role of Slc7a9 in maintaining AA and metabolic homeostasis, contributing to kidney injury. Supported by the Department of Veteran Affairs I01 BX004024-05 (to AS) grant. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.