Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Department of General Internal Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Phytomedicine. 2024 Sep;132:155632. doi: 10.1016/j.phymed.2024.155632. Epub 2024 May 22.
Type 2 cardiorenal syndrome (CRS) is a progressive renal insufficiency in patients with chronic heart failure, but its pathophysiology is still unclear. The Chinese medicine Zhenwu Decoction plays an important role in the prevention and treatment of 2-CRS, however, its mechanism of action remains unknown.
The aim of this study was to investigate whether the ameliorative effect of ZWD on 2-CRS renal fibrosis is related to the modulation of miR-451 expression and thus mediating the TLR4/NF-κB/HIF-1α loop.
A type 2 CRS rat model was constructed using ligation of the left anterior descending branch of the coronary artery + 3/4 nephrectomy, and randomly divided into Control, Sham, Model, Captopril, ZWD-L, ZWD-M and ZWD-H groups.After 4 weeks of ZWD intervention, its effects on cardiac and renal functions of type 2 CRS rats were observed by hematuria and cardiac ultrasonography. Changes in kidney tissue morphology were observed by HE, Masson and PASM staining. The protein and mRNA expression of TLR4, NF-κB, HIF-1α and IκBα in kidney tissues were detected by immunohistochemistry and qPCR. Immunofluorescence was used to detect the protein expression of NF-κB and HIF-1α in renal tissues. Western blot and qPCR were used to detect the protein expression of MCP-1, ICAM-1, IL-1β, IL-6, TGF-β, α-SMA, FN, Smad2, Smad3, and E-cadherin in renal tissues. PCR was used to detect the protein expression of miR-451mRNA expression level in kidney tissues.
In this study, we found that ZWD was able to reduce the expression of Scr, BUN, NT-proBNP, and 24-hour quantitative urine protein, elevate LVEF, FS, CO, and reduce the level of LVIDS in type 2 CRS rats, as well as attenuate renal interstitial fibrosis and improve tubular swelling. In addition, Zhenwu Decoction up-regulated the expression of miR-451 in renal tissues and inhibited the expression of TLR4, NF-κB, and HIF-1α proteins and genes, which in turn inhibited the expression of inflammatory factors and fibrosis-related factors.
ZWD was able to up-regulate the expression of miR-451 in renal tissues, inhibit the TLR4/NF-κB/HIF-1α response loop, and then inhibit the expression of inflammatory factors and fibrosis-related factors, improve renal fibrosis, and delay the pathological process of type 2 CRS.
2 型心肾综合征（CRS）是慢性心力衰竭患者肾功能进行性下降，但其发病机制尚不清楚。中药真武汤在 2 型 CRS 的防治中发挥着重要作用，但其作用机制尚不清楚。
本研究旨在探讨真武汤对 2 型 CRS 肾纤维化的改善作用是否与 miR-451 表达的调节有关，从而介导 TLR4/NF-κB/HIF-1α 环。
采用结扎左前降支冠状动脉+3/4 肾切除术构建 2 型 CRS 大鼠模型，随机分为对照组、假手术组、模型组、卡托普利组、真武低剂量组、真武中剂量组和真武高剂量组。4 周后真武汤干预后，通过血尿和心脏超声观察真武汤对 2 型 CRS 大鼠心肾功能的影响。通过 HE、Masson 和 PASM 染色观察肾组织形态学变化。采用免疫组化和 qPCR 检测肾组织 TLR4、NF-κB、HIF-1α 和 IκBα 的蛋白和 mRNA 表达。免疫荧光法检测肾组织 NF-κB 和 HIF-1α 的蛋白表达。Western blot 和 qPCR 检测肾组织 MCP-1、ICAM-1、IL-1β、IL-6、TGF-β、α-SMA、FN、Smad2、Smad3 和 E-cadherin 的蛋白表达。PCR 检测肾组织 miR-451mRNA 表达水平。
本研究发现，真武汤能降低 2 型 CRS 大鼠血肌酐、尿素氮、NT-proBNP 和 24 小时定量尿蛋白水平，提高左室射血分数、短轴缩短率、心输出量和降低左室收缩末期内径，减轻肾间质纤维化，改善肾小管肿胀。此外，真武汤能上调肾组织 miR-451 的表达，抑制 TLR4、NF-κB 和 HIF-1α 蛋白和基因的表达，进而抑制炎症因子和纤维化相关因子的表达。
真武汤能上调肾组织 miR-451 的表达，抑制 TLR4/NF-κB/HIF-1α 反应环，进而抑制炎症因子和纤维化相关因子的表达，改善肾纤维化，延缓 2 型 CRS 的病理过程。
