Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-B signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKβ, I B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-B signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-B signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.

中文翻译：

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糖酵解酶 PFKFB3 通过促进组蛋白乳酰化介导的 NF-κB 家族激活来驱动肾纤维化


肾脏中持续升高的糖酵解已被证明会促进慢性肾脏病（CKD）。然而，其基本机制仍不清楚。在这里，我们观察到 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3 (PFKFB3)，一种关键的糖酵解酶，在缺血再灌注损伤 (IRI) 后在肾近端肾小管细胞 (PTC) 中显着诱导。小鼠以及 CKD 患者的多种病因中。 PFKFB3表达与肾纤维化严重程度呈正相关。此外，慢性肾病患者和小鼠的尿乳酸/肌酸水平和肾乳酸水平分别升高。在 IRI 小鼠模型中，PTC 特异性删除 PFKFB3 显着降低肾脏乳酸水平，减轻炎症和纤维化，并保留肾功能。在 PFKFB3 杂合缺陷小鼠或用 PFKFB3 抑制剂治疗的小鼠中观察到类似的保护作用。从机制上讲，源自 PFKFB3 介导的肾小管糖酵解重编程的乳酸显着增强了组蛋白乳酰化，特别是 H4K12la，它在 Ikbkb、Rela 和 Relb 等 NF-B 信号基因的启动子处富集，激活其转录并促进炎症反应。此外，PTC 特异性删除 PFKFB3 抑制 IRI 肾脏中 IKKβ、IB α 和 p65 的激活。此外，H4K12la 水平升高与 CKD 患者的肾脏炎症和纤维化呈正相关。这些发现表明，肾小管 PFKFB3 可能通过促进 H4K12la 介导的基因转录及其激活，在增强 NF-B 信号传导方面发挥双重作用。因此，针对肾小管细胞中 PFKFB3 介导的 NF-B 信号通路可能是 CKD 治疗的新策略。