BACKGROUND Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS. METHODS Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis. RESULTS G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation. CONCLUSION Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.

中文翻译：

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凋亡信号调节激酶1的抑制通过减少心肌肾综合征大鼠模型中的肥大和纤维化来改善左心室功能障碍。

背景技术由于当前的治疗仍然不是最理想的，因此心肾综合征（CRS）是全世界需要新疗法的主要健康负担。本研究评估了CRS大鼠模型中凋亡信号调节激酶1（ASK1）抑制的治疗潜力。方法成年雄性Sprague-Dawley大鼠在第4周接受了心肌梗塞（MI）手术，第4周进行了5/6次全肾切除术（STNx），以诱导诱发心肾功能不全模型。在第6周，将MI + STNx动物随机接受0.5％的羧甲基纤维素（车辆，n = 15，深水= 10）或G226（每天15 mg / kg，n = 11）。在治疗前第6周和终点（第14周）分别通过超声心动图和肾小球滤过率（GFR）评估心脏和肾脏功能。在组织分析之前在终点确定血流动力学测量值。结果与车辆相比，G226治疗可减轻左心室（LV）缩短和后壁厚度的绝对变化。G226还减轻了预紧力可招募中风功的减少。G226治疗后，心肌横断面积增加，心脏间质纤维化，心脏胶原I和III的免疫反应性以及心脏TIMP-2活化显着降低。尽管我们并未观察到GFR的改善，但G226显着降低了肾间质纤维化，减少了肾胶原I和-IV，肾损伤分子1免疫反应性以及巨噬细胞浸润和SMAD2磷酸化。结论在CRS大鼠模型中，抑制ASK1可改善左室功能障碍，并减少心脏肥大和心肾纤维化。这表明ASK1是在CRS背景下具有治疗潜力的关键途径。