钠-葡萄糖共转运蛋白2（SGLT2）抑制剂在非糖尿病慢性肾脏病（CKD）模型中的肾脏保护机制尚不明确。实验共分为五组：假手术大鼠，5/6肾切除术（5/6Nx）后接受安慰剂治疗的大鼠；5/6Nx + 替米沙坦（5mg/kg/天），5/6Nx + 依帕列酮（3mg/kg/天）；5/6Nx + 依帕列酮（15mg/kg/天）。治疗持续95天。依帕列酮对基线估计肾小球滤过率（eGFR）的变化显示出剂量依赖性的有益效果。尿白蛋白与肌酐比值同样呈剂量依赖性改善。依帕列酮的两种剂量均改善了肾脏形态损伤参数，如肾间质纤维化和肾小球硬化。5/6肾切除术导致尿腺苷排泄的大幅减少，这是肾小管-肾小球反馈机制（TGF）的替代参数。依帕列酮导致尿腺苷排泄呈剂量依赖性增加。尿腺苷排泄与肾间质纤维化呈负相关，与eGFR呈正相关。免疫组化分析显示，依帕列酮对CD8+和CD4+T细胞以及CD68+细胞（巨噬细胞）无影响。为进一步探讨潜在机制，采用了非假设驱动方法。RNA测序后的定量实时聚合酶链反应显示，安慰剂治疗的5/6Nx大鼠中，补体成分1Q亚组件A链（C1qa）以及补体成分1Q亚组件C链（C1qc）基因表达上调，而依帕列酮治疗抑制了这种上调。总之，依帕列酮介导的非糖尿病CKD肾脏保护作用是由于剂量依赖性激活TGF以及依帕列酮对补体系统的影响。
The mechanisms of nephroprotection in non-diabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham operated rats, placebo treated rats with 5/6 nephrectomy (5/6Nx); 5/6Nx + telmisartan (5mg/kg/day), 5/6Nx + empagliflozin (3mg/kg/day); 5/6Nx + empagliflozin (15mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of estimated glomerular filtration rate (eGFR). The urinary albumin to creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback mechanism (TGF). Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with interstitial kidney fibrosis and positively correlated with eGFR. Immunohistochemical analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T-cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a non-hypothesis driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1qa) as well as complement component 1Q subcomponent C chain (C1qc) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin mediated-nephroprotection in non-diabetic CKD is due to a dose dependent activation of the TGF as well as empagliflozin mediated effects on the complement system.
