Abstract

Abstract Background and Aims Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to attenuate several types of acute kidney injury (AKI) in animal models [1–3]. However, the mechanisms underlying their renoprotective effects remain to be clarified. Previous studies had identified ferroptosis as the primary cell death pathway for folic acid-induced AKI in mice [4]. Referring to that report, we previously reported that teneligliptin, a DPP-4 inhibitor, ameliorates folic acid-induced AKI. In the present study, we investigated whether teneligliptin attenuates folic acid-induced tubular cell death through its anti-ferroptotic properties. Method In in vitro experiments, we used HK-2 cells, human proximal tubular epithelial cells. HK-2 cells were co-cultured with folic acid and z-VAD-FMK (zVAD), an apoptosis inhibitor; Necrostatin-1s (Nec-1s), a necroptosis inhibitor; Ferrostatin-1 (Fer-1), a ferroptosis inhibitor; or teneligliptin. Co-incubation of erastin, a ferroptosis inducer, and teneligliptin was also performed. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted on HK-2 cells to assess cell viability. Results Fer-1, but not z-VAD or Nec-1s, inhibited folic acid-induced cell death (Fig. 1A-C), indicating that ferroptosis contributes to folic acid-induced tubular cell death, rather than apoptosis or necroptosis. Teneligliptin also inhibited folic acid- and erastin-induced tubular cell death (Fig. 1D,E), suggesting that the DPP-4 inhibitor inhibits folic acid-induced tubular cell death via its anti-ferroptotic properties. Conclusion DPP-4 inhibitor prevents folic acid-induced tubular cell death by inhibiting ferroptosis in vitro, which may contribute to the attenuation of AKI in vivo.

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