已证明肾脏中持续升高的糖酵解可促进慢性肾脏疾病(CKD)。然而,潜在的机制仍不清楚.这里,我们观察到6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶3(PFKFB3),一种关键的糖酵解酶,在小鼠缺血再灌注损伤(IRI)后,肾近端肾小管细胞(PTCs)被显著诱导,以及CKD患者的多种病因。PFKFB3的表达与肾脏纤维化的严重程度呈正相关。此外,CKD患者和小鼠表现出增加的尿乳酸/肌酸水平和肾乳酸,分别。PFKFB3的PTCs特异性缺失显著降低了肾乳酸水平,减轻炎症和纤维化,并在IRI小鼠模型中保留肾功能。在具有PFKFB3杂合缺陷的小鼠或用PFKFB3抑制剂治疗的小鼠中观察到类似的保护作用。机械上,来自PFKFB3介导的管状糖酵解重编程的乳酸显着增强了组蛋白的乳酸,尤其是H4K12la,富含NF-κB信号基因如Ikbkb的启动子,瑞拉,Relb,激活它们的转录并促进炎症反应。Further,PFKFB3的PTCs特异性缺失抑制IKKβ的活化,IκBα,和IRI肾脏中的p65。此外,CKD患者H4K12la水平升高与肾脏炎症和纤维化呈正相关。这些发现表明,管状PFKFB3可能通过促进H4K12la介导的基因转录及其激活在增强NF-κB信号传导中起双重作用。因此,在肾小管细胞中靶向PFKFB3介导的NF-κB信号通路可能是CKD治疗的新策略.
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-κB 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 κ 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-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the
PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.