Fig. 6: A small-molecule Cdkl5 inhibitor mitigates AKI.

a In vitro kinase assays were carried out for cell-cycle-related kinases and CDKL5 for the indicated inhibitors at a single concentration of 1 µM. Kinase activity is presented as a heat map, where blue indicates no inhibition (high kinase activity), while red indicates kinase inhibition (low kinase activity). AST-487 was found to inhibit CDKL5, without affecting the activity of cell-cycle-related kinases. Data presented here are the mean of three independent experiments. b C57BL/6 mice were treated with either vehicle or AST-487 through oral administration followed by examination of Cdkl5 activity in renal tissues. Data are presented as individual data points (n = 5 biologically independent samples), from one out of two independent experiments, all producing similar results. c–e Bilateral renal ischemia was induced in wild-type C57BL/6 mice for 30 min followed by reperfusion for indicated timepoints. Mice were treated with either vehicle or AST-487 (25 mg/kg, oral gavage) 6 h post ischemia, followed by assessment of renal function and damage. c Blood urea nitrogen, d serum creatinine, and e renal histological analysis (H&E), Data presented (c–e) are cumulative of three independent experiments (n = 8). f–h Wild-type C57BL/6 mice were injected with cisplatin (30 mg/kg, i.p.) followed by treatment with either vehicle or AST-487 (25 mg/kg, oral gavage) 6 h later, followed by assessment of renal function and damage at indicated timepoints. Data presented (e–h) are cumulative of two out of four independent experiments (n = 8) that showed similar results. i Western blot analysis of renal tissues indicated that AST-487 suppresses Sox9 phosphorylation and increases Sox9 stability in vivo. Blots are representative of three independent experiments. In all the bar graphs, experimental values are presented as mean ± s.e.m. The height of error bar = 1 s.e. and p < 0.05 was indicated as statistically significant. One-way ANOVA followed by Dunnett’s (b) or Tukey’s multiple-comparison test (c–h) was carried out, and statistical significance is indicated by *p < 0.05, **p < 0.01, ***p < 0.001. Source data are provided as a Source Data file.