Kim Soojeong, Kim Sung Jun, Yoon Hye Eun, Chung Sungjin, Choi Bum Soon, Park Cheol Whee, Shin Seok Joon
1. Division of of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea.
2. Division of of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea.
Int J Med Sci. 2015 Oct 21;12(11):891-904. doi: 10.7150/ijms.13187. eCollection 2015.
A newly developed angiotensin II receptor blocker, fimasartan, is effective in lowering blood pressure through its action on the renin-angiotensin system. Renal interstitial fibrosis, believed to be due to oxidative injury, is an end-stage process in the progression of chronic kidney disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to regulate cellular oxidative stress and induce expression of antioxidant genes. In this study we investigated the role of Nrf2 in fimasartan-mediated antioxidant effects in mice with renal fibrosis induced by unilateral ureteral obstruction (UUO).
UUO was induced surgically in mice, followed by either no treatment with fimasartan or the intraperitoneal administration of fimasartan (3 mg/kg/day). On day 7, we evaluated the changes in the renin-angiotensin system (RAS) and the expression of Nrf2 and its downstream antioxidant genes, as well as renal inflammation, apoptosis, and fibrosis in the obstructed kidneys. The effect of fimasartan on the Nrf2 pathway was also investigated in HK-2 cells stimulated by tumor necrosis factor-α.
The mice with surgically induced UUO showed increased renal inflammation and fibrosis as evidenced by histopathologic findings and total collagen content in the kidney. These effects were attenuated in the obstructed kidneys of the fimasartan-treated mice. Fimasartan treatment inhibited RAS activation and the expression of Nox1, Nox2, and Nox4. In contrast, fimasartan upregulated the renal expression of Nrf2 and its downstream signaling molecules (such as NQO1; HO-1; GSTa2 and GSTm3). Furthermore, it increased the expression of antioxidant enzymes, including CuSOD, MnSOD, and catalase. The fimasartan-treated mice had significantly less apoptosis on TUNEL staining, with decreased levels of pro-apoptotic protein and increased levels of anti-apoptotic protein. In the HK-2 cells, fimasartan treatment inhibited RAS activation, decreased expression of mitogen-activated protein kinases (MAPKs), and upregulated the Nrf2 pathway.
These results suggest that fimasartan has beneficial effects in reducing renal oxidative stress, inflammation, and fibrosis. Possible mechanisms to explain these effects are inhibition of RAS and MAPKs and upregulation of Nrf2 signaling, with subsequent induction of antioxidant pathways.
新开发的血管紧张素II受体阻滞剂法米沙坦通过作用于肾素-血管紧张素系统有效降低血压。肾间质纤维化被认为是由氧化损伤所致，是慢性肾脏病进展的终末期过程。已知核因子红细胞2相关因子2（Nrf2）可调节细胞氧化应激并诱导抗氧化基因的表达。在本研究中，我们调查了Nrf2在法米沙坦介导的单侧输尿管梗阻（UUO）诱导的肾纤维化小鼠抗氧化作用中的作用。
通过手术诱导小鼠发生UUO，然后不给法米沙坦治疗或腹腔注射法米沙坦（3mg/kg/天）。在第7天，我们评估了肾素-血管紧张素系统（RAS）的变化、Nrf2及其下游抗氧化基因的表达，以及梗阻肾脏中的肾炎症、细胞凋亡和纤维化情况。还在肿瘤坏死因子-α刺激的HK-2细胞中研究了法米沙坦对Nrf2途径的影响。
手术诱导UUO的小鼠肾炎症和纤维化增加，肾脏组织病理学结果和总胶原蛋白含量证明了这一点。在法米沙坦治疗的小鼠的梗阻肾脏中，这些影响减弱。法米沙坦治疗抑制了RAS激活以及Nox1、Nox2和Nox4的表达。相反，法米沙坦上调了肾脏中Nrf2及其下游信号分子（如NQO1、HO-1、GSTa2和GSTm3）的表达。此外，它增加了抗氧化酶的表达，包括铜超氧化物歧化酶、锰超氧化物歧化酶和过氧化氢酶。法米沙坦治疗的小鼠在TUNEL染色上凋亡明显减少，促凋亡蛋白水平降低，抗凋亡蛋白水平升高。在HK-2细胞中，法米沙坦治疗抑制了RAS激活，降低了丝裂原活化蛋白激酶（MAPK）的表达，并上调了Nrf2途径。
这些结果表明，法米沙坦在减轻肾脏氧化应激、炎症和纤维化方面具有有益作用。解释这些作用的可能机制是抑制RAS和MAPK以及上调Nrf2信号，随后诱导抗氧化途径。
