PDF(Pubmed)
Abstract：
Sodium glucose co-transporter-2 (SGLT2) inhibitors stimulate renal excretion of sodium and glucose and exert renal protective effects in patients with (non-)diabetic chronic kidney disease (CKD) and may as well protect against acute kidney injury (AKI). The mechanism behind this kidney protective effect remains unclear. Juxtaglomerular cells of renin lineage (CoRL) have been demonstrated to function as progenitors for multiple adult glomerular cell types in kidney disease. This study assesses the impact of SGLT2 inhibition on the repopulation of glomerular cells by CoRL and examines their phenotypic commitment.
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.
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.
摘要：
目的：钠葡萄糖共转运体-2(SGLT2)抑制剂可刺激(非)糖尿病慢性肾脏病(CKD)患者肾脏钠和葡萄糖的排泄，发挥肾脏保护作用，并可能对急性肾损伤(AKI)具有保护作用。这种肾脏保护作用背后的机制尚不清楚。肾素谱系（CoRL）的肾小球旁细胞已被证明可作为肾脏疾病中多种成年肾小球细胞类型的祖细胞。这项研究评估了SGLT2抑制对CoRL肾小球细胞再增殖的影响，并检查了它们的表型承诺。
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。
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。
