Département de Médecine, Université de Montréal, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Tour Viger-Pavillon R, 900 Saint Denis Street, Montréal, Quebec H2X 0A9, Canada.
Division of Nephrology, Department of Internal Medicine, University of Michigan, 1560 MSRB II, 1150 West Medical Center Drive, SPC5676, Ann Arbor, MI 48109, U.S.A.
Clin Sci (Lond). 2021 Apr 16;135(7):943-961. doi: 10.1042/CS20210094.
Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44 mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP.
临床试验表明，钠/葡萄糖协同转运蛋白 2（SGLT2）抑制剂（SGLT2i）可改善肾功能，但 SGLT2 表达的分子调控尚不完全清楚。在这里，我们研究了肾内肾素-血管紧张素系统（RAS）对 SGLT2 表达的作用。在肾病综合征研究网络（NEPTUNE，n=163）的成年非糖尿病参与者中，多变量线性回归分析显示 SGLT2 mRNA 与血管紧张素原（AGT）、肾素和血管紧张素转换酶（ACE）mRNA 水平显著相关（P<0.001）。在体外，血管紧张素 II（Ang II）以剂量依赖的方式刺激 HK-2，人永生化肾近端肾小管细胞（RPTCs）中的 SGLT2 表达；洛沙坦和抗氧化剂抑制了它。在其 RPTCs 中特异性过表达 Agt 的转基因（Tg）小鼠以及单次皮下注射 Ang II（1.44 mg/kg）的 WT 小鼠中，Sglt2 表达增加。此外，在 WT 小鼠中通过渗透微型泵输注 Ang II（1000 ng/kg/min）4 周会增加收缩压（SBP）、肾小球硬化、肾小管间质纤维化和白蛋白尿；卡格列净（Cana，15 mg/kg/天）逆转了这些变化，但 SBP 除外。Ang II+Cana 组的葡萄糖排泄分数（FeGlu）高于 WT+Cana 组，而 Sglt2 表达相似。我们的数据表明，肾内 RAS 与 SGLT2 表达之间存在联系，并且 SGLT2i 可改善 Ang II 诱导的肾脏损伤，而不依赖于 SBP。
