Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel.
Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel.
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DOI：
10.3390/biomedicines11020305
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发表时间：
2023-01-21
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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作者：
糖尿病肾病是2型糖尿病(T2 DM)患者发病的主要原因。新的数据表明，高血压是T2 DM的常见并发症，可能会恶化糖尿病肾病的预后。虽然二甲双胍是治疗2型糖尿病的常用处方药，但它的血压调节能力还没有很好的文献记载。本研究的目的是观察二甲双胍对盐负荷高血压糖尿病db/db小鼠血压的影响。16周龄的雄性和雌性糖尿病db/db小鼠分别被放置在代谢笼中，然后随机分为对照组(生理盐水)或二甲双胍治疗组。我们评价了二甲双胍对盐诱导的高血压和db/db小鼠肾病进展的降压作用。我们观察到二甲双胍使高血压糖尿病小鼠的收缩压正常化。从机制上讲，二甲双胍治疗减少了肾组织蛋白酶B的表达。组织蛋白酶B的低表达与上皮钠通道(ENaC)的表达和活性降低、钠滞留，从而控制高血压相关。此外，我们还发现，糖尿病小鼠的尿液细胞外小泡(EV)富含组织蛋白酶B。与使用赋形剂治疗的高血压糖尿病小鼠相比，将肾集合管细胞暴露于从二甲双胍治疗的db/db小鼠或组织蛋白酶B基因敲除小鼠分离的尿液EV后，阿米洛利敏感的跨皮细胞电流显著减弱。总之，我们的研究确定了二甲双胍通过调节组织蛋白酶B-ENaC轴在糖尿病肾病中的一种新的降压作用。
Diabetic nephropathy is the primary cause of morbidity in type 2 diabetes mellitus (T2DM) patients. New data indicate that hypertension, a common comorbidity in T2DM, can worsen outcomes of diabetic nephropathy. While metformin is a commonly prescribed drug for treating type 2 diabetes, its blood pressure regulating ability is not well documented. The aim of this study was to investigate the effect of metformin on normalizing blood pressure in salt-loaded hypertensive diabetic db/db mice. Sixteen-week-old male and female diabetic db/db mice were individually placed in metabolic cages and then randomized to a control vehicle (saline) or metformin treatment group. We evaluated the blood pressure reducing ability of metformin in salt-induced hypertension and progression of nephropathy in db/db mice. We observed that metformin- normalized systolic blood pressure in hypertensive diabetic mice. Mechanistically, metformin treatment reduced renal cathepsin B expression. Low cathepsin B expression was associated with reduced expression and activity of the epithelial sodium channel (ENaC), sodium retention, and thus control of hypertension. In addition, we identified that urinary extracellular vesicles (EVs) from the diabetic mice are enriched in cathepsin B. Compared to treatment with urinary EVs of vehicle-treated hypertensive diabetic mice, the amiloride-sensitive transepithelial current was significantly attenuated upon exposure of renal collecting duct cells to urinary EVs isolated from metformin-treated db/db mice or cathepsin B knockout mice. Collectively, our study identifies a novel blood pressure reducing role of metformin in diabetic nephropathy by regulating the cathepsin B-ENaC axis.
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影响因子：
5.5
作者：
Chacko KM;Nouri MZ;Schramm WC;Malik Z;Liu LP;Denslow ND;Alli AA
通讯作者：
Alli AA
影响因子：
4
作者：
Pavlov TS;Levchenko V;Ilatovskaya DV;Li H;Palygin O;Pastor-Soler NM;Hallows KR;Staruschenko A
通讯作者：
Staruschenko A
DOI：
10.1016/j.ecl.2013.09.005
发表时间：
2014-03
影响因子：
4.5
作者：
Lastra, Guido;Syed, Sofia;Kurukulasuriya, L. Romayne;Manrique, Camila;Sowers, James R.
通讯作者：
Sowers, James R.
影响因子：
--
作者：
GARG, LC;NARANG, N;MCARDLE, S
通讯作者：
MCARDLE, S
影响因子：
--
作者：
GREENE, AS;YU, ZY;COWLEY, AW
通讯作者：
COWLEY, AW