Klimontov Vadim V, Korbut Anton I, Taskaeva Iuliia S, Bgatova Nataliya P, Dashkin Maksim V, Orlov Nikolai B, Khotskina Anna S, Zavyalov Evgenii L, Klein Thomas
Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL-Branch of IC&G SB RAS), Novosibirsk 630060, Russia.
Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL-Branch of IC&G SB RAS), Novosibirsk 630060, Russia.
World J Diabetes. 2020 Dec 15;11(12):596-610. doi: 10.4239/wjd.v11.i12.596.
Modern guidelines recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease. However, the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood.
To estimate the effect of the SGLT2 inhibitor, empagliflozin (EMPA), on the structure of podocytes and nephrin expression in glomeruli in diabetic mice.
We treated 8-wk-old male mice with EMPA (10 mg/kg/d) or vehicle for 8 wk. Age-matched male mice were included as non-diabetic controls. Parameters of body composition, glycemic and lipid control, and plasma concentrations of leptin, insulin and glucagon were assessed. We evaluated renal hypertrophy as kidney weight adjusted to lean mass, renal function as plasma levels of creatinine, and albuminuria as the urinary albumin-to-creatinine ratio (UACR). Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure, respectively. Glomerular nephrin and transforming growth factor beta (TGF-β) were assessed by immunohistochemistry.
Severe obesity and hyperglycemia developed in mice prior to the start of the experiment; increased plasma concentrations of fructosamine, glycated albumin, cholesterol, leptin, and insulin, and elevated UACR were detected. Mesangial expansion, glomerular basement membrane thickening, and increased area of TGF-β staining in glomeruli were revealed in vehicle-treated mice. Podocytopathy was manifested by effacement of foot processes; nephrin-positive areas in glomeruli were reduced. EMPA decreased the levels of glucose, fructosamine and glycated albumin, UACR, kidney hypertrophy, mesangial expansion, glomerular basement membrane thickening, and glomerular TGF-β staining, alleviated podocytopathy and restored glomerular staining of nephrin.
These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease. The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.
现代指南推荐钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂作为2型糖尿病和慢性肾脏病患者的首选降糖药物。然而，SGLT2抑制剂肾脏保护作用的潜在机制尚未完全明确。
评估SGLT2抑制剂恩格列净（EMPA）对糖尿病小鼠足细胞结构和肾小球中nephrin表达的影响。
我们用EMPA（10 mg/kg/d）或赋形剂处理8周龄雄性小鼠8周。将年龄匹配的雄性小鼠作为非糖尿病对照。评估身体成分、血糖和血脂控制参数以及瘦素、胰岛素和胰高血糖素的血浆浓度。我们将肾脏重量调整为瘦体重来评估肾脏肥大，将血浆肌酐水平作为肾功能指标，将尿白蛋白与肌酐比值（UACR）作为蛋白尿指标。分别通过光学显微镜和透射电子显微镜研究肾脏结构，重点关注系膜体积和足细胞结构。通过免疫组织化学评估肾小球nephrin和转化生长因子β（TGF-β）。
在实验开始前，小鼠出现严重肥胖和高血糖；检测到果糖胺、糖化白蛋白、胆固醇、瘦素和胰岛素的血浆浓度升高，以及UACR升高。在接受赋形剂处理的小鼠中，观察到系膜扩张、肾小球基底膜增厚以及肾小球中TGF-β染色面积增加。足细胞病变表现为足突消失；肾小球中nephrin阳性区域减少。EMPA降低了血糖、果糖胺和糖化白蛋白水平、UACR、肾脏肥大、系膜扩张、肾小球基底膜增厚以及肾小球TGF-β染色，减轻了足细胞病变并恢复了肾小球nephrin染色。
这些数据表明，EMPA可减轻实验性糖尿病肾病中的足细胞病变。EMPA的抗蛋白尿作用可能归因于减轻足细胞损伤和增强nephrin表达。
