Objective This study aimed to investigate the role of Mep1a in unilateral ureteral obstruction (UUO)-induced renal injury and the underlying mechanisms.
Methods A UUO model was established in Mep1a knockout (KO) mice and wild-type littermates. Primary renal tubular epithelial cells were isolated and treated with transforming growth factor-β1 (TGF-β1), and Mep1a was knocked down by small interfering RNA. Macrophages were induced with interleukin-4 (IL-4). Renal fibrosis and pathological injury were evaluated by Masson’s trichrome staining, hematoxylin-eosin (H&E) staining, and Western blotting. Glycolysis was assessed by measuring extracellular acidification rate (ECAR) and lactate production. The AKT/HIF-1α pathway was examined by Western blotting, and AKT was reactivated with SC79.
Results Mep1a was upregulated in UUO-injured kidney tissues and TGF-β1-induced renal tubular epithelial cells, but showed no significant change in IL-4-induced macrophages. Mep1a knockout mice exhibited attenuated renal fibrosis and improved renal pathological injury compared with wild-type controls after UUO. In vitro, Mep1a knockdown reduced TGF-β1-induced upregulation of Collagen I, Collagen III, α-SMA, and vimentin in renal tubular epithelial cells. Mechanistically, Mep1a deficiency suppressed glycolysis and lactate accumulation during renal injury. Mep1a deficiency also downregulated AKT phosphorylation and HIF-1α expression in TGF-β1-induced renal tubular epithelial cells, and reactivation of AKT by SC79 abolished the inhibitory effects of Mep1a deficiency on Pfkfb3, Ldha, and Pfk1 mRNA levels.
Conclusion Mep1a deficiency alleviates UUO-induced renal injury by inhibiting EMT via blockade of glycolysis in an HIF-1α-dependent manner.
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Funding
National Natural Science Foundation of China(82300114)
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The Author(s), under exclusive licence to the Huazhong University of Science and Technology
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