Reduction of anaerobic glycolysis contributes to angiotensin II-induced podocyte injury with foot process effacement
Reduction of anaerobic glycolysis contributes to angiotensin II-induced podocyte injury with foot process effacement
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DOI：
10.1016/j.kint.2023.01.007
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发表时间：
2023-03-20
影响因子：
19.6
通讯作者：
Ding, Guohua
中科院分区：
文献类型：
--
作者：
Chen, Zhaowei;Zhu, Zijing;Ding, Guohua
肾素-血管紧张素系统的激活与足细胞损伤相关，并已被充分证明是慢性肾脏病进展的关键因素。足细胞能量代谢对于维持其生理功能至关重要。然而，肾素-血管紧张素系统激活是否通过扰乱足细胞的能量代谢促进慢性肾病进展尚不清楚。血管紧张素II是肾素-血管紧张素系统的主要活性分子，在慢性肾脏病的发生和进展中发挥着至关重要的作用，但其对足细胞代谢的影响仍不清楚。在这里，我们证明在体内和体外暴露于血管紧张素 II 的足细胞中，丙酮酸激酶 M2（一种关键的糖酵解酶）的表达迅速下降，并且糖酵解通量减少。小鼠足细胞特异性删除丙酮酸激酶 M2 会加重血管紧张素 II 诱导的肾小球和足细胞损伤，并伴有足突消失和蛋白尿。糖酵解的抑制伴随着三磷酸腺苷缺乏、细胞骨架重塑和足细胞凋亡。从机制上讲，我们发现血管紧张素 II 诱导的糖酵解障碍导致足突能量供应不足，导致足细胞损伤。此外，还发现高血压肾病和糖尿病肾病患者肾活检的足细胞中丙酮酸激酶 M2 表达降低。因此，我们的研究结果表明糖酵解激活是足细胞损伤的潜在治疗策略。
Activation of the renin-angiotensin system is associated with podocyte injury and has been well demonstrated as a pivotal factor in the progression of chronic kidney disease. Podocyte energy metabolism is crucial for maintaining their physiological functions. However, whether renin-angiotensin system activation promotes chronic kidney disease progression by disturbing the energy metabolism of podocytes has not been elucidated. Angiotensin II, the main active molecule of the renin-angiotensin system, plays a crucial role in chronic kidney disease initiation and progression, but its impact on podocyte metabolism remains unclear. Here, we demonstrate a rapid decrease in the expression of pyruvate kinase M2, a key glycolytic enzyme, and reduced glycolytic flux in podocytes exposed to angiotensin II in vivo and in vitro. Podocyte-specific deletion of pyruvate kinase M2 in mice aggravated angiotensin II-induced glomerular and podocyte injury with foot process effacement and proteinuria. The inhibition of glycolysis was accompanied by adenosine triphosphate deficiency, cytoskeletal remodeling and podocyte apoptosis. Mechanistically, we found that angiotensin II-induced glycolysis impairment contributed to an insufficient energy supply to the foot process, leading to podocyte injury. Additionally, pyruvate kinase M2 expression was found to be reduced in podocytes from kidney biopsies of patients with hypertensive nephropathy and diabetic kidney disease. Thus, our findings suggest that glycolysis activation is a potential therapeutic strategy for podocyte injury.