肾脏纤维化被认为是慢性肾脏病 (CKD) 向肾衰竭进展的基本病理生理过程。20-羟基二十碳四烯酸 (20-HETE) 在调节肾脏的血管反应和蛋白尿的进展方面起着至关重要的作用。然而,20-HETE 在肾纤维化中的作用在很大程度上尚未得到探索。在目前的研究中,我们假设如果 20-HETE 在肾纤维化的进展中具有重要作用,那么 20-HETE 合成抑制剂可能对肾纤维化有效。为验证我们的假设,本研究调查了一种新型选择性 20-HETE 合成抑制剂 TP0472993 对小鼠叶酸和梗阻性肾病后肾纤维化发展的影响。用 0 剂量的 TP0472993 进行慢性治疗。每天两次 3 和 3 mg/kg 可减轻叶酸肾病和单侧输尿管梗阻 (UUO) 小鼠的肾纤维化程度,如 Masson 三色染色和肾胶原蛋白含量减少所示。此外,TP0472993 减少了肾脏炎症,显着降低了白介素-1肾组织中的β (IL-1 β ) 和肿瘤坏死因子 α (TNF- α ) 水平。TP0472993 的长期治疗还降低了 UUO 小鼠肾脏中细胞外信号调节激酶 1/2 (ERK1/2) 和信号转导和转录激活因子 3 (STAT3) 的活性。我们的观察表明,用 TP0472993 抑制 20-HETE 的产生可通过减少 ERK1/2 和 STAT3 信号通路来抑制肾纤维化进展,这表明 20-HETE 合成抑制剂可能是一种针对 CKD 的新型治疗选择。
重要性声明
在这项研究中,我们证明了使用 TP0472993 对 20-羟基二十碳四烯酸 (20-HETE) 合成的药理学阻断抑制了小鼠叶酸和梗阻性肾病后肾纤维化的进展,表明 20-HETE 可能具有关键作用在肾纤维化的发病机制中。TP0472993 有可能成为一种治疗慢性肾病的新型疗法。
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Renoprotective Effect of TP0472993, a Novel and Selective 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, in Mouse Models of Renal Fibrosis
Kidney fibrosis is considered the essential pathophysiological process for the progression of chronic kidney disease (CKD) toward renal failure. 20-Hydroxyeicosatetraenoic acid (20-HETE) has crucial roles in modulating the vascular response in the kidney and the progression of albuminuria. However, the roles of 20-HETE in kidney fibrosis are largely unexplored. In the current research, we hypothesized that if 20-HETE has important roles in the progression of kidney fibrosis, 20-HETE synthesis inhibitors might be effective against kidney fibrosis. To verify our hypothesis, this study investigated the effect of a novel and selective 20-HETE synthesis inhibitor, TP0472993, on the development of kidney fibrosis after folic acid– and obstructive-induced nephropathy in mice. Chronic treatment with TP0472993 at doses of 0.3 and 3 mg/kg twice a day attenuated the degree of kidney fibrosis in the folic acid nephropathy and the unilateral ureteral obstruction (UUO) mice, as demonstrated by reductions in Masson’s trichrome staining and the renal collagen content. In addition, TP0472993 reduced renal inflammation, as demonstrated by markedly reducing interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) levels in the renal tissue. Chronic treatment with TP0472993 also reduced the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) in the kidney of UUO mice. Our observations indicate that inhibition of 20-HETE production with TP0472993 suppresses the kidney fibrosis progression via a reduction in the ERK1/2 and STAT3 signaling pathway, suggesting that 20-HETE synthesis inhibitors might be a novel treatment option against CKD.
SIGNIFICANCE STATEMENT
In this study, we demonstrate that the pharmacological blockade of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis using TP0472993 suppresses the progression of kidney fibrosis after folic acid– and obstructive-induced nephropathy in mice, indicating that 20-HETE might have key roles in the pathogenesis of kidney fibrosis. TP0472993 has the potential to be a novel therapeutic approach against chronic kidney disease.