the metabolic defect in glycolysis in peritubular endothelial cells may be effective in the treatment of CKD. Background Peritubular endothelial cell dropout leading to microvascular rarefaction is a common manifestation of CKD. The role of metabolism reprogramming in peritubular endothelial cell loss in CKD is undetermined. Methods Single-cell sequencing and metabolic analysis were used to characterize the metabolic profile of peritubular endothelial cells from patients with CKD and from CKD mouse models. In vivo and in vitro models demonstrated metabolic reprogramming in peritubular endothelial cells in conditions of CKD and its contribution to microvascular rarefaction. Results In this study, we identified glycolysis as a top dysregulated metabolic pathway in peritubular endothelial cells from patients with CKD. Specifically, CKD peritubular endothelial cells were hypoglycolytic while displaying an antiangiogenic response with decreased proliferation and increased apoptosis. The hypoglycolytic phenotype of peritubular endothelial cells was recapitulated in CKD mouse models and in peritubular endothelial cells stimulated by hydrogen peroxide. Mechanically, oxidative stress, through activating a redox sensor kruppel-like transcription factor 9, downregulated the glycolytic activator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase expression, thereby reprogramming peritubular endothelial cells toward a hypoglycolytic phenotype. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase overexpression in peritubular endothelial cells restored hydrogen peroxide–induced reduction in glycolysis and cellular ATP levels and enhanced the G1/S cell cycle transition, enabling peritubular endothelial cells to improve proliferation and reduce apoptosis. Consistently, restoration of peritubular endothelial cell glycolysis in CKD mice, by overexpressing endothelial Pfkfb3, reversed the antiangiogenic response in peritubular endothelial cells and protected the kidney from microvascular rarefaction and fibrosis. By contrast, suppression of glycolysis by endothelial Pfkfb3 deletion exacerbated microvascular rarefaction and fibrosis in CKD mice. Conclusions Our study revealed a disrupted regulation of glycolysis in peritubular endothelial cells as an initiator of microvascular rarefaction in CKD. Restoration of peritubular endothelial cell glycolysis in CKD kidney improved microvascular rarefaction and ameliorated fibrotic lesions....

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肾小管周围内皮细胞的糖酵解和 CKD 中的微血管稀疏化


肾小管周围内皮细胞糖酵解的代谢缺陷可能对治疗 CKD 有效。背景 肾小管周围内皮细胞脱落导致微血管稀疏是 CKD 的常见表现。代谢重编程在 CKD 肾小管周围内皮细胞丢失中的作用尚未确定。方法 采用单细胞测序和代谢分析来表征 CKD 患者和 CKD 小鼠模型的肾小管周围内皮细胞的代谢特征。体内和体外模型证明了在 CKD 条件下肾小管周围内皮细胞的代谢重编程及其对微血管稀疏的贡献。结果 在这项研究中，我们确定糖酵解是 CKD 患者肾小管周围内皮细胞中最重要的失调代谢途径。具体来说，CKD 肾小管周围内皮细胞是低糖酵解的，同时表现出抗血管生成反应，增殖减少和细胞凋亡增加。在 CKD 小鼠模型和过氧化氢刺激的肾小管周围内皮细胞中概括了肾小管周围内皮细胞的低糖酵解表型。在机械上，氧化应激通过激活氧化还原传感器 kruppel 样转录因子 9，下调糖酵解激活剂 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶的表达，从而将肾小管周围内皮细胞重新编程为低糖酵解表型。肾小管周围内皮细胞中 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶过表达恢复了过氧化氢诱导的糖酵解和细胞 ATP 水平降低，并增强了 G1/S 细胞周期转变，使肾小管周围内皮细胞能够改善增殖并减少细胞凋亡。 一致地，通过过表达内皮 Pfkfb3 恢复 CKD 小鼠的肾小管周围内皮细胞糖酵解，逆转了肾小管周围内皮细胞的抗血管生成反应，并保护肾脏免受微血管稀疏和纤维化的影响。相比之下，内皮 Pfkfb3 缺失对糖酵解的抑制加剧了 CKD 小鼠的微血管稀疏和纤维化。结论 我们的研究揭示了肾小管周围内皮细胞中糖酵解的调节被破坏是 CKD 中微血管稀疏的起始剂。恢复 CKD 肾肾小管周围内皮细胞糖酵解改善了微血管稀疏并改善了纤维化病变。