Experiments were performed in Ren1cre-tdTomato lineage-trace mice. Either 5/6 nephrectomy (5/6NX) modeling CKD or bilateral ischaemia reperfusion injury (bIRI) mimicking AKI was applied, while the SGLT2 inhibitor empagliflozin (10 mg/kg) was administered daily via oral gavage for 14 days.
Both 5/6NX and bIRI-induced kidney injury increased the number of glomerular CoRL-derived cells. SGLT2 inhibition improved kidney function after 5/6NX, indicated by decreased blood creatinine and urea levels, but not after bIRI. In line with this, empagliflozin in 5/6NX animals resulted in less glomerulosclerosis, while it did not affect histopathological features in bIRI. Treatment with empagliflozin resulted in an increase in the number of CoRL-derived glomerular cells in both 5/6NX and bIRI conditions. Interestingly, SGLT2 inhibition led to more CoRL-derived podocytes in 5/6NX animals, whereas empagliflozin-treated bIRI mice presented with increased levels of parietal epithelial and mesangial cells derived from CoRL.
We conclude that SGLT2 inhibition by empagliflozin promotes CoRL-mediated glomerular repopulation with selective CoRL-derived cell types depending on the type of experimental kidney injury. These findings suggest a previously unidentified mechanism that could contribute to the renoprotective effect of SGLT2 inhibitors.
方法:在Ren1cre-tdTomato谱系追踪小鼠中进行实验。采用5/6肾切除术(5/6NX)模拟CKD或双侧缺血再灌注损伤(bIRI)模拟AKI,而SGLT2抑制剂empagliflozin(10mg/kg)每天通过口服灌胃给药14天。
结果:5/6NX和bIRI诱导的肾损伤均增加了肾小球CoRL衍生细胞的数量。SGLT2抑制改善5/6NX后的肾功能,血肌酐和尿素水平下降,但不是在BIRI之后。与此相符,5/6NX动物中的empagliflozin导致较少肾小球硬化,虽然它不影响bIRI的组织病理学特征。在5/6NX和bIRI条件下,用依帕列净治疗均导致CoRL衍生的肾小球细胞数量增加。有趣的是,SGLT2抑制导致5/6NX动物中更多CoRL衍生的足细胞,而依帕列净治疗的bIRI小鼠表现出来自CoRL的顶叶上皮和系膜细胞水平升高。
结论:我们得出结论,依帕格列净对SGLT2的抑制作用可促进CoRL介导的肾小球再增殖,其选择性CoRL衍生的细胞类型取决于实验性肾损伤的类型。这些发现提示了先前未被鉴定的机制,其可能有助于SGLT2抑制剂的肾脏保护作用。