Department of Nephrology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
FASEB J. 2022 Aug;36(8):e22427. doi: 10.1096/fj.202200573R.
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.
赖氨酰氧化酶（LOX）是一种依赖铜的单胺氧化酶，其主要功能是在细胞外基质（ECM）中使胶原蛋白发生共价交联。有证据表明，LOX 与癌症和一些纤维化疾病有关。我们最近发现，血清 LOX 是肾纤维化的潜在诊断生物标志物，但 LOX 如何被调控以及如何促进肾纤维化的机制尚不清楚。本研究表明：（1）纤维化肾脏中 LOX 的表达增加，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 诱导的胶原蛋白的增加沉积和交联。（3）LOX 在肾纤维化中受β-arrestin-ERK-STAT3 通路的调控。STAT3 是 AT1R-β-arrestin-ERK 的下游，ERK 进入细胞核并激活 STAT3-pY705，但不激活 STAT3-pS727。（4）STAT3 的核亚细胞易位和与 LOX 启动子的结合可能是 LOX 表达上调的原因。（5）体内用 BAPN 抑制 LOX 可抑制 LOX 的上调，减少胶原过度交联，并改善缺血损伤后的肾纤维化。总之，这些观察结果表明，LOX 通过催化胶原蛋白过度交联在肾纤维化的发展中起关键作用。因此，靶向 LOX 的策略可能是开发治疗肾纤维化的新途径。
