Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China.
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China.
Kidney Int. 2023 Apr;103(4):735-748. doi: 10.1016/j.kint.2023.01.007. Epub 2023 Jan 31.
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.
肾素-血管紧张素系统的激活与足细胞损伤有关，并且已被充分证明是慢性肾脏病进展的关键因素。足细胞的能量代谢对于维持其生理功能至关重要。然而，肾素-血管紧张素系统的激活是否通过干扰足细胞的能量代谢来促进慢性肾脏病的进展尚未阐明。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起着关键作用，但它对足细胞代谢的影响尚不清楚。在这里，我们在体内和体外实验中证明，血管紧张素 II 会导致足细胞中关键糖酵解酶丙酮酸激酶 M2 的表达迅速下降，糖酵解通量降低。在小鼠中特异性敲除丙酮酸激酶 M2 会加剧血管紧张素 II 诱导的肾小球和足细胞损伤，导致足突融合和蛋白尿。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。在机制上，我们发现血管紧张素 II 诱导的糖酵解损伤导致足突能量供应不足，从而导致足细胞损伤。此外，我们还发现高血压肾病和糖尿病肾病患者肾活检中的足细胞丙酮酸激酶 M2 表达降低。因此，我们的研究结果表明，糖酵解的激活是治疗足细胞损伤的一种潜在治疗策略。
