SLC38A6 expression in renal tubular cells accelerates cisplatin‐induced acute kidney injury by promoting cell apoptosis

Acute kidney injury (AKI) is a major public health issue. Solute carrier family 38 member 6 (SLC38A6) is known to mediate Na⁺-dependent net uptake and efflux of small neutral amino acids, but the role it plays in AKI still needs to be explored. In this study, we generated mice with Slc38a6 genetically deleted in tubular epithelial cells by crossing Slc38a6^fl/fl mice with KspCre mice, which are transgenic mice that express Cre recombinase exclusively in tubular epithelial cells in the kidney and developing genitourinary tract. The mice were intraperitoneally injected with cisplatin. Separately, SLC38A6 was knocked down in HK-2 cells using siRNA, followed by treatment with cisplatin. Blood urea nitrogen (BUN) and Serum Creatinine (SCr) levels were used to measure renal function, and PAS and H&E staining, along with detection of NGAL expression was used to assess kidney injury. Tunel staining and the expression of apoptosis-related proteins were used to detect kidney cell apoptosis. Transcriptome sequencing was performed to explore the mechanism underlying our phenotypic observations, and lipid deposition was determined using Oil Red O staining. The expression of key enzymes of the fatty acid β-oxidation (FAO) pathway was detected using Western blotting and RT-qPCR. After induction of AKI, Slc38a6^fl/flKspCre mice exhibited improved renal function, alleviated kidney injury, and decreased tubular cell apoptosis. Similarly, knocking down SLC38A6 in HK-2 cells significantly abrogated apoptosis induced by AKI. Transcriptome sequencing data confirmed that several pathways involved in fatty acid metabolism were activated in Slc38a6^fl/flKspCre mice. Both Slc38a6^fl/flKspCre mice and SLC38A6-knocked down HK-2 cells exhibited decreased lipid deposition and increased expression of key enzymes of the FAO pathway. We therefore conclude that SLC38A6-deficiency alleviates cisplatin-induced AKI by decreasing cell apoptosis and promoting FAO.