Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin.
Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin.
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DOI：
10.3390/ijms18020305
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发表时间：
2017-01-31
影响因子：
5.6
通讯作者：
Lee SK
中科院分区：
文献类型：
--
作者：
Kim H;Baek CH;Lee RB;Chang JW;Yang WS;Lee SK
内质网（ER）应激越来越多地被认为是纤维化的调节因子。氯沙坦是一种血管紧张素II受体阻滞剂，已被广泛应用于慢性肾脏疾病的首选治疗。我们推测氯沙坦的抗纤维化作用是通过SIRT1（沉默交配型信息调节2同源物1）血红素加氧酶-1（HO-1）/硫氧还蛋白途径抑制ER应激介导的。采用肾小管细胞、衣霉素（TM）诱导的ER应激和单侧输尿管梗阻（UUO）小鼠模型。Western blot和免疫组化染色检测ER应激的表达。ER应激由化学ER应激诱导剂衣霉素和非化学诱导剂如TGF-β、血管紧张素II、高糖和白蛋白诱导。氯沙坦可通过HO-1和硫氧还蛋白上调SIRT1的表达，抑制TM诱导的GRP78和p-eIF2 α的表达，从而抑制TM诱导的内质网应激。Losartan还可通过非化学诱导剂抑制内质网应激。在这两种动物模型中，氯沙坦降低了肾小管GRP78的表达，这是取消了sirtinol（SIRT1抑制剂）预处理。Sirtinol也能阻断氯沙坦对UUO诱导的肾纤维化的抑制作用。这些发现为氯沙坦的肾脏保护作用提供了新的见解，并表明SIRT1，HO-1和硫氧还蛋白可能是过度ER应激条件下肾脏疾病的潜在药理学靶点。
Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.