Departments of Physiology and of Medicine and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana, USA,
Departments of Physiology and of Medicine and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Am J Nephrol. 2019;49(4):331-342. doi: 10.1159/000499597. Epub 2019 Mar 28.
Hypertension and renal injury are common complications of type 2 diabetes mellitus (T2DM). Hyperglycemia stimulates renal proximal tubular angiotensinogen (AGT) expression via elevated oxidative stress contributing to the development of high blood pressure and diabetic nephropathy. The sodium glucose cotransporter 2 (SGLT2) in proximal tubules is responsible for the majority of glucose reabsorption by renal tubules. We tested the hypothesis that SGLT2 inhibition with canagliflozin (CANA) prevents intrarenal AGT augmentation and ameliorates kidney injury and hypertension in T2DM.
We induced T2DM in New Zealand obese mice with a high fat diet (DM, 30% fat) with control mice receiving regular fat diet (ND, 4% fat). When DM mice exhibited > 350 mg/dL blood glucose levels, both DM- and ND-fed mice were treated with 10 mg/kg/day CANA or vehicle by oral gavage for 6 weeks. We evaluated intrarenal AGT, blood pressure, and the development of kidney injury.
Systolic blood pressure in DM mice (133.9 ± 2.0 mm Hg) was normalized by CANA (113.9 ± 4.0 mm Hg). CANA treatment ameliorated hyperglycemia-associated augmentation of renal AGT mRNA (148 ± 21 copies/ng RNA in DM, and 90 ± 16 copies/ng RNA in DM + CANA) and protein levels as well as elevation of urinary 8-isoprostane levels. Tubular fibrosis in DM mice (3.4 ± 0.9-fold, fibrotic score, ratio to ND) was suppressed by CANA (0.9 ± 0.3-fold). Furthermore, CANA attenuated DM associated increased macrophage infiltration and cell proliferation in kidneys of DM mice.
CANA prevents intrarenal AGT upregulation and oxidative stress and which may mitigate high blood pressure, renal tubular fibrosis, and renal inflammation in T2DM.
高血压和肾脏损伤是 2 型糖尿病（T2DM）的常见并发症。高血糖通过升高氧化应激刺激肾脏近端小管血管紧张素原（AGT）的表达，导致高血压和糖尿病肾病的发生。近端肾小管中的钠-葡萄糖共转运蛋白 2（SGLT2）负责肾脏肾小管对葡萄糖的大部分重吸收。我们检验了这样一个假设，即通过用坎格列净（CANA）抑制 SGLT2 可以防止肾内 AGT 增加，并改善 T2DM 中的肾脏损伤和高血压。
我们用高脂肪饮食（DM，30%脂肪）诱导新西兰肥胖小鼠发生 T2DM，对照组小鼠给予常规脂肪饮食（ND，4%脂肪）。当 DM 小鼠的血糖水平超过 350mg/dL 时，DM 和 ND 喂养的小鼠均通过口服灌胃给予 10mg/kg/天 CANA 或载体，持续 6 周。我们评估了肾内 AGT、血压和肾脏损伤的发展情况。
DM 小鼠的收缩压（133.9±2.0mm Hg）通过 CANA 恢复正常（113.9±4.0mm Hg）。CANA 治疗改善了与高血糖相关的肾 AGT mRNA（DM 中为 148±21 拷贝/ng RNA，DM + CANA 中为 90±16 拷贝/ng RNA）和蛋白水平的增加，以及尿 8-异前列腺素水平的升高。DM 小鼠的肾小管纤维化（3.4±0.9 倍，纤维化评分，与 ND 的比值）被 CANA 抑制（0.9±0.3 倍）。此外，CANA 减弱了 DM 相关的巨噬细胞浸润和 DM 小鼠肾脏的细胞增殖。
CANA 可防止肾内 AGT 的上调和氧化应激，从而减轻 T2DM 中的高血压、肾小管纤维化和肾脏炎症。
