■血管紧张素受体-脑啡肽抑制剂(ARNI)是心力衰竭的既定治疗方法。然而,对于心肾综合征(CRS),ARNI是否具有单独使用肾素-血管紧张素系统抑制剂以外的肾脏保护作用尚未完全阐明.这里,我们研究了ARNI对有明显蛋白尿的CRS模型小鼠心脏和肾脏的影响,并确定了ARNI诱导肾脏保护的潜在机制.
■C57BL6小鼠接受慢性血管紧张素II输注,肾切除术,和盐负荷(ANS);他们开发了CRS表型,并分为载体处理(ANS-载体),沙库巴曲/缬沙坦治疗(ANS-ARNI),和两种不同剂量的缬沙坦治疗(ANS-VALM,ANS-VALH)组。治疗四周后,对各组的心脏和肾脏进行评估.ANS-媒介物组显示心脏纤维化,心功能不全,明显的白蛋白尿,和肾脏纤维化。与缬沙坦治疗组相比,ANS-ARNI组显示心脏纤维化和心脏功能障碍减少。然而,关于以蛋白尿和纤维化为特征的肾脏保护作用,ARNI不如缬沙坦有效。肾脏转录组分析表明,与ANS-VALM组相比,ANS-ARNI组的磷酸肌醇3-激酶(PI3K)-AKT信号通路显着增强。在ARNI中添加PI3K抑制剂治疗可改善肾损伤至与ANS-VALM相当的水平,同时保留ARNI的优良心脏保护作用。
■PI3K通路激活已被确定为CRS病理学中ARNI治疗下影响残余肾损伤的关键机制,同时ARNI治疗阻断PI3K通路是治疗伴有明显蛋白尿的CRS的潜在治疗策略。
UNASSIGNED: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection.
UNASSIGNED: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI.
UNASSIGNED: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.