Lysyl oxidase promotes renal fibrosis via accelerating collagen cross-link driving by β-arrestin/ERK/STAT3 pathway.
Lysyl oxidase promotes renal fibrosis via accelerating collagen cross-link driving by β-arrestin/ERK/STAT3 pathway.
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赖氨酰氧化酶通过 β-arrestin/ ERK/STAT3 途径加速胶原蛋白交叉链接，促进肾纤维化
DOI：
10.1096/fj.202200573r
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发表时间：
2022-08
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赖氨酰氧化酶（LOX）是一种铜依赖性单胺氧化酶，其主要功能是共价交联细胞外基质（ECM）中的胶原蛋白。有证据表明，LOX与癌症和一些纤维化病症有关。我们最近发现，血清LOX是一个潜在的诊断肾纤维化的生物标志物，但LOX的调节机制，并有助于肾纤维化仍然是未知的。目前的研究表明：（1）LOX表达在纤维化肾脏中增加，包括缺血再灌注损伤（IRI-）、单侧输尿管梗阻（UUO-）和叶酸（FA-）诱导的纤维化肾脏以及肾纤维化患者的人肾石蜡包埋切片。(2)在IRI-、UUO-和FA-肾脏中观察到LOX诱导的胶原沉积和交联增加。(3)LOX在肾纤维化中受β-arrestin-ERK-STAT 3通路调节。STAT 3是AT 1 R-β-arrestin-ERK的下游，ERK进入细胞核并激活STAT 3-pY 705，但不激活STAT 3-pS 727。(4)STAT 3核转位和与LOX启动子的结合可能是LOX表达上调的原因。(5)在体内用BAPN对LOX进行药理学抑制可抑制LOX的上调，减少胶原过度交联并改善缺血性损伤后的肾纤维化。总的来说，这些观察结果表明LOX通过催化胶原过度交联在肾纤维化的发展中起重要作用。因此，靶向LOX的策略可能是开发抗肾纤维化疗法的新途径。
Lysyl oxidase (LOX) is a copper‐dependent monoamine oxidase whose primary function is the covalent cross‐linking of collagen in the extracellular matrix (ECM). Evidence has shown that LOX is associated with cancer and some fibrotic conditions. We recently found that serum LOX is a potential diagnostic biomarker for renal fibrosis, but the mechanism by which LOX is regulated and contributes to renal fibrosis remains unknown. The current study demonstrates the following: (1) LOX expression was increased in fibrotic kidneys including ischemia‐reperfusion injury‐(IRI‐), unilateral ureteral obstruction‐(UUO‐), and folic acid‐ (FA‐) induced fibrotic kidneys as well as in the paraffin‐embedded sections of human kidneys from the patients with renal fibrosis. (2) The increasing deposition and cross‐linking of collagen induced by LOX was observed in IRI‐, UUO‐ and FA‐kidneys. (3) LOX was regulated by the β‐arrestin‐ERK‐STAT3 pathway in renal fibrosis. STAT3 was the downstream of AT1R‐β‐arrestin‐ERK, ERK entered the nucleus and activated STAT3‐pY705 but not STAT3‐pS727. (4) STAT3 nuclear subtranslocation and binding to the LOX promoter may be responsible for the upregulation of LOX expression. (5) Pharmacologic inhibition of LOX with BAPN in vivo inhibited the upregulation of LOX, decreased collagen over cross‐linking and ameliorated renal fibrosis after ischemic injury. Collectively, these observations suggest that LOX plays an essential role in the development of renal fibrosis by catalyzing collagen over cross‐linking. Thus, strategies targeting LOX could be a new avenue in developing therapeutics against renal fibrosis.