Albuminuria enhances NHE3 and NCC via stimulation of mitochondrial oxidative stress/angiotensin II axis.
Albuminuria enhances NHE3 and NCC via stimulation of mitochondrial oxidative stress/angiotensin II axis.
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蛋白尿通过刺激线粒体氧化应激/血管紧张素 II 轴增强 NHE3 和 NCC
DOI：
10.18632/oncotarget.9972
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Zhang A
中科院分区：
文献类型：
--
作者：
Jia Z;Zhuang Y;Hu C;Zhang X;Ding G;Zhang Y;Rohatgi R;Hua H;Huang S;He JC;Zhang A
盐和水的不平衡是肾脏疾病常见且具有挑战性的并发症，其致病机制仍然难以捉摸。采用白蛋白超载小鼠模型，我们发现白蛋白尿增强了小鼠肾脏中 NHE3 和 NCC 的表达，但不增强其他转运蛋白的表达，这与血管紧张素原 (AGT)/血管紧张素转换酶 (ACE)/血管紧张素 (Ang) II 级联的刺激一致。在肾小管细胞的原代培养物中，白蛋白直接刺激 AGT/ACE/Ang II 并上调 NHE3 和 NCC 表达。用 ACE 抑制剂阻断 Ang II 的产生可以使细胞中 NHE3 和 NCC 的上调正常化。有趣的是，白蛋白超载显着降低了线粒体超氧化物歧化酶（SOD2），并且SOD2模拟物（MnTBAP）的施用使NHE3、NCC和受白蛋白尿影响的AGT/ACE途径成分的表达正常化，表明线粒体源性氧化应激在调节肾素-血管紧张素系统（RAS）和肾钠转运蛋白中的关键作用。此外，功能数据显示 Na 和 Cl 的尿液排泄减少以及对特定 NCC 抑制剂的反应增强，进一步支持了白蛋白过载后钠转运蛋白的调节结果。更重要的是，在蛋白尿患者肾脏中也观察到 NHE3 和 NCC 的上调以及 ACE/Ang II 信号通路的激活，这表明我们的动物模型准确地复制了人类状况。总而言之，这些新发现表明蛋白尿对于通过线粒体氧化应激启动的 ACE/Ang II 级联刺激来重置肾盐处理具有重要意义。这也可能为解决蛋白尿性肾病中的盐和水失衡提供新颖、有效的治疗靶点。
Imbalance of salt and water is a frequent and challenging complication of kidney disease, whose pathogenic mechanisms remain elusive. Employing an albumin overload mouse model, we discovered that albuminuria enhanced the expression of NHE3 and NCC but not other transporters in murine kidney in line with the stimulation of angiotensinogen (AGT)/angiotensin converting enzyme (ACE)/angiotensin (Ang) II cascade. In primary cultures of renal tubular cells, albumin directly stimulated AGT/ACE/Ang II and upregulated NHE3 and NCC expression. Blocking Ang II production with an ACE inhibitor normalized the upregulation of NHE3 and NCC in cells. Interestingly, albumin overload significantly reduced mitochondrial superoxide dismutase (SOD2), and administration of a SOD2 mimic (MnTBAP) normalized the expression of NHE3, NCC, and the components of AGT/ACE pathway affected by albuminuria, indicating a key role of mitochondria-derived oxidative stress in modulating renin-angiotensin system (RAS) and renal sodium transporters. In addition, the functional data showing the reduced urinary excretion of Na and Cl and enhanced response to specific NCC inhibitor further supported the regulatory results of sodium transporters following albumin overload. More importantly, the upregulation of NHE3 and NCC and activation of ACE/Ang II signaling pathway were also observed in albuminuric patient kidneys, suggesting that our animal model accurately replicates the human condition. Taken together, these novel findings demonstrated that albuminuria is of importance in resetting renal salt handling via mitochondrial oxidative stress-initiated stimulation of ACE/Ang II cascade. This may also offer novel, effective therapeutic targets for dealing with salt and water imbalance in proteinuric renal diseases.
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DOI：
10.1097/01.asn.0000028839.52271.df
发表时间：
2002-09-01
影响因子：
13.6
作者：
Nishiyama, A;Seth, DM;Navar, LG
通讯作者：
Navar, LG
DOI：
10.1161/hypertensionaha.109.134783
发表时间：
2009-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Panico C;Luo Z;Damiano S;Artigiano F;Gill P;Welch WJ
通讯作者：
Welch WJ
影响因子：
13.6
作者：
Erkan, Elif;Devarajan, Prasad;Schwartz, George J.
通讯作者：
Schwartz, George J.
影响因子：
19.6
作者：
van der Lubbe, Nils;Lim, Christina H.;Hoorn, Ewout J.
通讯作者：
Hoorn, Ewout J.
影响因子：
19.6
作者：
Wolf, G;Schroeder, R;Stahl, RAK
通讯作者：
Stahl, RAK