Finerenone Attenuates Endothelial Dysfunction and Albuminuria in a Chronic Kidney Disease Model by a Reduction in Oxidative Stress.
Finerenone Attenuates Endothelial Dysfunction and Albuminuria in a Chronic Kidney Disease Model by a Reduction in Oxidative Stress.
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DOI：
10.3389/fphar.2018.01131
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发表时间：
2018
影响因子：
5.6
通讯作者：
Fernández-Alfonso MS
中科院分区：
文献类型：
--
作者：
González-Blázquez R;Somoza B;Gil-Ortega M;Martín Ramos M;Ramiro-Cortijo D;Vega-Martín E;Schulz A;Ruilope LM;Kolkhof P;Kreutz R;Fernández-Alfonso MS
蛋白尿是与氧化应激增加相关的肾血管损伤的早期标志。慕尼黑Wistar Frömter （MWF）大鼠是慢性肾脏疾病（CKD）的模型，其表现出与低一氧化氮可用性相关的内皮功能障碍。我们假设，新的高选择性，非甾体矿物皮质激素受体（MR）拮抗剂，细烯酮，逆转内皮功能障碍和微量白蛋白尿。12周龄MWF （MWF-C; MWF-FIN）和年龄匹配的正常蛋白尿Wistar （W-C; W-FIN）大鼠分别给予细烯酮（FIN, 10 mg/kg/day p.o）或对照(C)治疗4周。治疗最后一天测定收缩压（SBP）和蛋白尿。芬纳酮可使MWF患者蛋白尿降低约40%，并显著降低收缩压。与W-C环相比，MWF-C环对去甲肾上腺素（NA）和血管紧张素II （Ang II）的收缩更大，对乙酰胆碱（Ach）的松弛更小。由于磷酸化Akt和eNOS的上调以及NO可用性的增加，这些改变被细烯酮逆转到W-C控制水平。罗布麻素和3-氨基-1,2,4-三唑显著降低MWF-C环对NA或Ang II的收缩，但对MWF-FIN环无明显影响。因此，MWF-FIN环中mn -超氧化物歧化酶（SOD）和Cu/Zn-SOD蛋白水平显著升高，而p22phox、p47phox和过氧化氢酶水平无显著差异。MWF-FIN大鼠肾脏总SOD活性升高。综上所述，芬烯酮通过提高一氧化氮的生物利用度和降低超氧阴离子水平来改善内皮功能障碍，这是由于SOD活性的上调。这与肾脏超氧化物歧化酶活性增加和蛋白尿减少有关。
Albuminuria is an early marker of renovascular damage associated to an increase in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic kidney disease (CKD), which exhibits endothelial dysfunction associated to low nitric oxide availability. We hypothesize that the new highly selective, non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C; MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic blood pressure (SBP) and albuminuria were determined the last day of treatment. Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF. Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C rings. These alterations were reversed by finerenone to W-C control levels due to an upregulation in phosphorylated Akt and eNOS, and an increase in NO availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein levels were observed in rings of MWF-FIN, without differences in p22phox, p47phox or catalase levels. Total SOD activity was increased in kidneys from MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through an enhancement in NO bioavailability and a decrease in superoxide anion levels due to an upregulation in SOD activity. This is associated with an increase in renal SOD activity and a reduction of albuminuria.
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影响因子：
168.9
作者：
Matsushita, Kunihiro;van der Velde, Marije;Astor, Brad C.;Woodward, Mark;Levey, Andrew S.;de Jong, Paul E.;Coresh, Josef;Gansevoort, Ron T.
通讯作者：
Gansevoort, Ron T.
影响因子：
3
作者：
Kolkhof, Peter;Delbeck, Martina;Schaefer, Stefan
通讯作者：
Schaefer, Stefan
影响因子：
4.9
作者：
Hermansa, Marc M. H.;Henry, Ronald M. A.;Stehouwer, Coen D. A.
通讯作者：
Stehouwer, Coen D. A.
影响因子：
2.9
作者：
HISSIN, PJ;HILF, R
通讯作者：
HILF, R
影响因子：
7.3
作者：
Gil-Ortega, M.;Garcia-Prieto, C. F.;Somoza, B.
通讯作者：
Somoza, B.