Abstract: TH-PO0213
SLC6A19 Inhibition Drives a Protective Proximal Tubule Metabolic State Complementary to SGLT2 Inhibition
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Crasta, Sheela, Maze Therapeutics Inc, South San Francisco, California, United States
- Kim, Young Chul, University of California San Diego, La Jolla, California, United States
- Liu, Serena, Maze Therapeutics Inc, South San Francisco, California, United States
- Billing, Anja M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Xi, Yannan, Maze Therapeutics Inc, South San Francisco, California, United States
- Sarwaikar, Richa, Maze Therapeutics Inc, South San Francisco, California, United States
- Oe, Yuji, University of California San Diego, La Jolla, California, United States
- Graham, Robert R., Maze Therapeutics Inc, South San Francisco, California, United States
- Hosur, Raghavendra, Maze Therapeutics Inc, South San Francisco, California, United States
- Sanman, Laura, Maze Therapeutics Inc, South San Francisco, California, United States
- Beattie, David T., Maze Therapeutics Inc, South San Francisco, California, United States
- Estrada, Karol, Maze Therapeutics Inc, South San Francisco, California, United States
- Ullman, Julie, Maze Therapeutics Inc, South San Francisco, California, United States
- Rinschen, Markus M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Vallon, Volker, University of California San Diego, La Jolla, California, United States
- Hoek, Maarten, Maze Therapeutics Inc, South San Francisco, California, United States
Background
SLC6A19 (B0AT1) is a sodium-dependent neutral amino acid transporter expressed in the small intestine and kidney proximal tubule (PT). Human loss-of-function (LOF) variants in SLC6A19 are associated with improved kidney function and reduced CKD progression. We previously showed that genetic ablation or pharmacologic SLC6A19 inhibition (SLC6A19i) in mice is protective in the aristolochic acid I (AAI) model of kidney injury and provides additional benefit when combined with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin. Here, we generate new multi-omics datasets to define mechanisms of SLC6A19 LOF–mediated renoprotection and its interaction with SGLT2i.
Methods
We generated a 367,565-cell single nucleus RNA-sequencing (snRNA-seq) dataset from kidneys of healthy and AAI-injured mice treated with the SLC6A19i MZ-402 and/or dapagliflozin. Cell type annotation using the mouse KPMP atlas enabled high-resolution characterization of PT injury and repair states. We also performed integrated proteomics, including whole-kidney proteomics, phosphoproteomics, and segment-specific PT-S1 and PT-S3 proteomics, in SLC6A19 KO mice, SGLT2i-treated mice, and the combination.
Results
Analyses of snRNAseq data showed that, at baseline, SLC6A19i and SGLT2i had minimal effects on healthy PT cell abundance. In contrast, AAI injury significantly altered PT cell states, reducing healthy PT-S2 and PT-S3 populations by 8-fold and 4-fold, respectively, while increasing adaptive and failed-repair PT states by 8-fold and 16-fold, respectively (FDR < 0.01 for all). SLC6A19i, and to a lesser extent SGLT2i, reduced failed-repair PT cells while increasing healthy PT cells. Proteomic analyses showed that SLC6A19 KO altered PT transporter expression and upregulated proteins involved in peroxisomal and mitochondrial fatty acid oxidation (FAO; e.g., EHHADH, CPT1A) in the PT-S1. In contrast, SGLT2i altered glucose handling protein expression (e.g., suppression of SGLT1) in the PT-S3.
Conclusion
Loss of SLC6A19 function promotes PT rewiring toward productive repair during AAI injury and exhibits distinct effects from SGLT2i. These findings support SLC6A19 as a promising therapeutic target in CKD and suggest potential complementary benefit when combined with SGLT2i.