Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells
Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells
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DOI：
10.1038/hr.2013.157
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发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Iwano, Masayuki
中科院分区：
文献类型：
--
作者：
Mikami, Daisuke;Kimura, Hideki;Iwano, Masayuki
替米沙坦是一种 1 型血管紧张素 II 受体阻滞剂 (ARB)，最近据报道通过充当过氧化物酶体增殖物激活受体 (PPAR)-δ 激活剂来促进小鼠脂肪分解，尽管在临床研究中，它也被认为激活 PPAR-c 是其多效作用的主要原因。本研究的目的是探讨替米沙坦是否激活内源性 PPAR-δ，从而在人系膜细胞 (HMC) 中发挥抗纤维化作用。对人肾活检标本的免疫组织化学分析显示，在具有中度增殖性变化的肾小球 HMC 中检测到 PPAR-δ 蛋白。在 HMC 中，GW0742（一种真正的 PPAR-δ 激动剂）和替米沙坦均剂量依赖性地增强 PPAR 反应元件（PPRE）-荧光素酶活性，并且这些增加被 GSK0660（一种特定的 PPAR-δ 拮抗剂）减弱，但不能被 GW9662（一种 PPAR-c 拮抗剂）减弱。替米沙坦还上调与脂肪酸氧化相关的 PPAR-δ 靶基因的表达；即心型-脂肪酸结合蛋白和解偶联蛋白-2。这些效应受到 PPAR-δ 拮抗作用和 PPAR-δ 基因沉默的抑制。转化生长因子-β 1 (TGF-β 1) 增加纤溶酶原激活剂抑制剂-1 (PAI-1)、TGF-β 1 和 IV 型胶原的表达。 PAI-1 的表达至少部分是由细胞外信号调节激酶 (ERK) 的磷酸化介导的。替米沙坦抑制 TGF-β1 刺激的 PAI-1 和 IV 型胶原表达以及 ERK 磷酸化，并且这些作用被 PPAR-δ 拮抗作用减弱，而依普罗沙坦（一种非 PPAR 激活 ARB）不影响 TGF-β1 刺激的 PAI-1 表达。这些结果表明，在 HMC 中，替米沙坦激活内源性 PPAR-δ，并可能通过以 PPAR-δ 依赖性方式减少 ERK 磷酸化来预防 TGF-β1 诱导的纤维化变化，因此可能有助于治疗患有肾脏和代谢疾病的高血压患者。
Telmisartan, an angiotensin II receptor type 1 blocker (ARB), was recently reported to promote lipolysis in mice by acting as a peroxisome proliferator-activated receptor (PPAR)-delta activator, although in clinical studies, it has also been recognized to activate PPAR-c as a major cause of its pleiotropic actions. The aim of this study was to investigate whether telmisartan activates endogenous PPAR-delta and thereby exerts anti-fibrotic effects in human mesangial cells (HMC). Immunohistochemical analysis of human renal biopsy specimens revealed that PPAR-delta protein was detected in the HMC of glomeruli with moderately proliferative changes. In the HMC, both GW0742, an authentic PPAR-delta agonist, and telmisartan enhanced PPAR response element (PPRE)-luciferase activity dose dependently, and these increases were blunted by GSK0660, a specific PPAR-delta antagonist, but not by GW9662, a PPAR-c antagonist. Telmisartan also upregulated the expression of PPAR-delta target genes related to fatty acid oxidation; that is, heart type-fatty acid-binding protein and uncoupling protein-2. These effects were inhibited by both PPAR-delta antagonism and PPAR-delta gene silencing. Transforming growth factor-beta 1 (TGF-beta 1) increased the expression of plasminogen activator inhibitor-1 (PAI-1), TGF-beta 1 and collagen IV. The PAI-1 expression was mediated, at least in part by the phosphorylation of extracellular signal-regulated kinases (ERKs). Telmisartan suppressed TGF-beta 1-stimulated PAI-1 and collagen IV expression and ERK phosphorylation, and these effects were weakened by PPAR-delta antagonism, whereas eprosartan, a non-PPAR activating ARB, did not affect TGF-beta 1-stimulated PAI-1 expression. These results indicate that in HMC telmisartan activates endogenous PPAR-delta and may prevent TGF-beta 1-induced fibrotic changes by reducing ERK phosphorylation in a PPAR-delta-dependent manner, and thus, might be useful for treating hypertensive patients with renal and metabolic disorders.