INTRODUCTION AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors can have renoprotective effects in some acute kidney injury (AKI) models, but the mechanisms-of-action and their role in tubule recovery upon AKI remains speculative. We hypothesized that the DPP-4 inhibitor teneligliptin can accelerate tubular re-epithelialization after cisplatin-induced AKI by triggering cell cycle entry and completion of mitosis, i.e. proliferation of tubular epithelial cells.
METHODS: Isolated primary tubular cells were screened with a drug library to identify potential candidates to accelerate proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Proliferation of tubular cells was evaluated with cell cycle analysis and cell counting by flow cytometry. AKI was induced in rats by injecting 5mg/kg of cisplatin intravenously. Oral administration of 10mg/kg of teneligliptin, once a day, was started just before injecting cisplatin or from day 5 after cisplatin injection.
RESULTS: In vitro, teneligliptin and its optimal dose were selected based on the MTT screening assay (Fig.1). Teneligliptin promoted cell cycle entry into S/G2/M phase in primary tubular cells (Fig.2), which increased cell number (Fig.3). In vivo, the levels of serum creatinine (sCr)/ blood urea nitrogen (BUN) and cell death evaluated with the terminal uridine nick-end labeling (TUNEL)+ cells peaked at day 5 after cisplatin injection. The levels decreased at day 10, comparing to that of day 5; however, the increased levels sustained until day 14. Pretreatment of teneligliptin prevented the elevation of sCr/BUN level and decreased TUNEL+ cells at day 5. Post treatment of teneligliptin from day 5 decreased BUN level (Fig.4), kidney injury molecule-1 (kim-1) expression (Fig. 5) and collagen deposition (Fig. 6) at day 14.
CONCLUSIONS: The DPP-4 inhibitor teneligliptin accelerates recovery after toxic AKI by facilitating the proliferation of tubular cells.
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