Genetic Ablation of SLC6A19 Is Protective against Kidney Damage in Mouse Models of CKD

Background: SLC6A19 is a sodium-dependent neutral amino acid transporter expressed in the small intestine and proximal tubule of the kidney. SLC6A19 has emerged as a novel target for the treatment of CKD based on analyses of large human data sets that have identified a link between loss of function gene variants with protection from CKD, and that individuals carrying heterozygous putative loss-of-function (LOF) variants in SLC6A19 have improved eGFR while gain of function variants carriers have diminished eGFR. In agreement with the protection from CKD observed in humans, ablation of SLC6A19 in mice has been shown to protect animals from renal injury induced by the proximal tubule toxin aristolochic acid (AAI). Methods: Maze Therapeutics has developed a new SLC6A19 KO mouse model to further investigate published findings. These mice were tested in the AAI model of CKD and biomarkers of kidney injury were assessed. In order to understand mechanistically how SLC6A19 LOF protects from renal injury samples were evaluated using transcriptomic, metabolomic, and immunostaining assays. Results: When tested in the AAI CKD model the SLC6A19 KO mice were protected from chronic renal injury with evidence of normalization of kidney injury markers KIM1 and NGAL, as well as attenuation of UACR. Metabolomics from KO and WT animals reveals distinct redistribution of metabolic pathways consistent with SLC6A19’s role as an amino acid transporter. Transcriptomic analysis of kidney samples from the AAI study suggest KO protection is mediated through alterations in metabolic pathways including downregulation of glycolysis and upregulation of oxidative phosphorylation. Conclusion: Though the exact mechanism by which SLC6A19 LOF protects the kidney is not completely understood, we hypothesize this could be through a combination of decreasing workload on the proximal tubule, decreasing proximal tubule mTOR activity mediated by amino acid uptake, and decreasing intraglomerular pressure by restoring tubule-glomerular feedback via increased sodium delivery to distal regions of the nephron. In addition to direct effects on the kidney, reduction of SLC6A19 activity in the gut may lead to reduction of whole-body amino acid and metabolite intake that benefits multi-system physiology. Funding: Commercial Support - Maze Therapeutics