PFKFB3 downregulation aggravates Angiotensin II-induced podocyte detachment

Podocytes play a critical role in maintaining normal glomerular filtration, and podocyte loss from the glomerular basement membrane (GBM) initiates and worsens chronic kidney disease (CKD). However, the exact mechanism underlying podocyte loss remains unclear. Fructose-2,6-biphosphatase 3 (PFKFB3) is a bifunctional enzyme that plays crucial roles in glycolysis, cell proliferation, cell survival, and cell adhesion. This study aimed to determine the role of PFKFB3 in angiotensin II (Ang II) kidney damage. We found that mice infused with Ang II developed glomerular podocyte detachment and impaired renal function accompanied by decreased PFKFB3 expression <i>in vivo</i> and <i>in vitro</i>. Inhibition of PFKFB3 with the PFKFB3 inhibitor 3PO further aggravated podocyte loss induced by Ang II. In contrast, activating PFKFB3 with the PFKFB3 agonist meclizine alleviated the podocyte loss induced by Ang II. Mechanistically, PFKFB3 knockdown likely aggravate Ang II-induced podocyte loss by suppressing talin1 phosphorylation and integrin beta1 subunit (ITGB1) activity. Conversely, PFKFB3 overexpression protected against Ang II-induced podocyte loss. These findings suggest that Ang II leads to a decrease in podocyte adhesion by suppressing PFKFB3 expression, and indicates a potential therapeutic target for podocyte injury in CKD.

足细胞（podocytes）在维持正常肾小球滤过功能中发挥关键作用，而从肾小球基底膜（glomerular basement membrane, GBM）丢失的足细胞会启动并加重慢性肾脏病（chronic kidney disease, CKD）。但目前足细胞丢失的确切机制仍不明确。果糖-2,6-二磷酸酶3（Fructose-2,6-biphosphatase 3, PFKFB3）是一种双功能酶，在糖酵解、细胞增殖、细胞存活及细胞黏附过程中发挥关键作用。本研究旨在明确PFKFB3在血管紧张素II（angiotensin II, Ang II）所致肾损伤中的作用。我们发现，在体内和体外实验中，输注血管紧张素II的小鼠出现肾小球足细胞脱落及肾功能受损，同时伴随PFKFB3表达下调。使用PFKFB3抑制剂3PO抑制PFKFB3活性，会进一步加重血管紧张素II诱导的足细胞丢失；与之相反，使用PFKFB3激动剂美克洛嗪（meclizine）激活PFKFB3，则可减轻血管紧张素II诱导的足细胞丢失。机制研究显示，敲低PFKFB3可能通过抑制踝蛋白1（talin1）磷酸化及整合素β1亚基（integrin beta1 subunit, ITGB1）活性，加重血管紧张素II诱导的足细胞丢失；反之，过表达PFKFB3则可对抗血管紧张素II诱导的足细胞丢失。上述研究结果表明，血管紧张素II通过抑制PFKFB3表达降低足细胞黏附能力，为慢性肾脏病足细胞损伤的潜在治疗靶点提供了新的参考依据。