AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen 518060, China.
AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen 518060, China; Department of Nephrology, the First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):860-870. doi: 10.1016/j.bbadis.2017.12.028. Epub 2017 Dec 19.
Angiotensin II (AngII) plays an important role in the pathogenesis of hypertension and associated renal injuries. To elucidate the molecular mechanism by which AngII induces renal damage, we found that AngII infusion significantly induced CYP4A14 expression in renal proximal tubule cells (RPTCs) with marked increases in blood pressure and proteinuria. Renal production of the major CYP4A metabolite, 20-HETE, was also significantly increased in the AngII-treated mice. Compared to wild-type (WT) mice, CYP4A14 knockout (CYP4A14) mice exhibited significantly lower levels of blood pressure, renal 20-HETE production, proteinuria and renal fibrosis following AngII infusion. Furthermore, AngII-induced renal expression of profibrotic genes and proinflammatory genes was significantly attenuated in CYP4A14 mice. In vitro studies using cultured RPTCs demonstrated that AngII significantly induced CYP4A14 expression and 20-HETE production via the MAPK signaling pathway. AngII treatment increased TGF-β and collagen expression, which was attenuated by the CYP4A inhibitor, TS-011. Moreover, 20-HETE treatment potently induced CYP4A14 expression and TGF-β and collagen levels. Collectively, these findings suggest that attenuated renal fibrosis in AngII-treated CYP4A14 mice may result from both reduced systemic blood pressure and renal 20-HETE production. Therefore, CYP4A14 may represent a useful target for the treatment of AngII-associated renal damage.
血管紧张素 II（AngII）在高血压和相关肾损伤的发病机制中起着重要作用。为了阐明 AngII 诱导肾损伤的分子机制，我们发现 AngII 输注可显著诱导肾近端小管细胞（RPTC）中 CYP4A14 的表达，同时显著增加血压和蛋白尿。AngII 处理的小鼠中肾产生的主要 CYP4A 代谢物 20-HETE 也显著增加。与野生型（WT）小鼠相比，CYP4A14 敲除（CYP4A14）小鼠在 AngII 输注后血压、肾 20-HETE 产生、蛋白尿和肾纤维化水平明显降低。此外，CYP4A14 小鼠中 AngII 诱导的致纤维化基因和促炎基因的肾表达明显减弱。体外培养的 RPTC 研究表明，AngII 通过 MAPK 信号通路显著诱导 CYP4A14 表达和 20-HETE 产生。AngII 处理增加 TGF-β 和胶原蛋白表达，而 CYP4A 抑制剂 TS-011 可减弱这种表达。此外，20-HETE 处理可强力诱导 CYP4A14 表达和 TGF-β 及胶原蛋白水平。综上所述，这些发现表明，AngII 处理的 CYP4A14 小鼠肾纤维化减少可能是由于全身血压降低和肾 20-HETE 产生减少。因此，CYP4A14 可能是治疗 AngII 相关肾损伤的一个有用靶点。
