Cefadroxil targeting of SLC15A2/PEPT2 protects from colistin nephrotoxicity

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered interconnected syndromes, as AKI episodes may accelerate CKD progression and CKD increases the risk of AKI. Genome-wide association studies (GWAS) may identify novel actionable therapeutic targets. Human genome-wide association studies (GWAS) for AKI or CKD were combined with murine AKI transcriptomics datasets to identify 13 (ACACB, ACSM5, CNDP1, DPEP1, GATM, SLC6A12, AGXT2L1, SLC15A2, CTSS, ICAM1, ITGAX, ITGAM, PPM1J) potentially actionable therapeutic targets to modulate kidney disease severity across species and across the AKI-CKD spectrum. Among them, SLC15A2, encoding the cell membrane proton-coupled peptide transporter 2 (PEPT2), was prioritized for data mining and functional intervention studies in vitro and in vivo because of its known function to transport nephrotoxic drugs such as colistin and the possibility for targeting with small molecules already in clinical use, such as cefadroxil. Data mining disclosed that SLC15A2 was upregulated in the tubulointerstitium of human CKD, including diabetic nephropathy, and the upregulation was localized to proximal tubular cells. Colistin elicited cytotoxicity and a proinflammatory response in cultured human and murine proximal tubular cells that was decreased by concomitant exposure to cefadroxil. In proof-of-concept in vivo studies, cefadroxil protected from colistin nephrotoxicity in mice. The GWAS association of SLC15A2 with human kidney disease may be actionable and related to the modifiable transport of nephrotoxins causing repeated subclinical episodes of AKI and/or chronic nephrotoxicity.