慢性肾脏病(CKD)进展与持续的氧化应激有关,它通过形成不能被NO激活的氧化且无血红素的apo-sGC来损害NO-sGC-cGMP信号级联。Runcaciguat(BAY1101042)是一部小说,强力,和选择性sGC激活剂,其结合并激活氧化且无血红素的sGC,从而在氧化应激下恢复NO-sGC-cGMP信号传导。因此,runcaciguat可能是CKD/DKD非常有效的治疗选择。在ZSF1大鼠作为CKD/DKD模型中研究了runcaciguat的潜在肾脏保护作用。以高血压为特征,高血糖症,肥胖,和胰岛素抵抗。ZSF1大鼠每天口服治疗长达12周的runcaciguat(1、3、10mg/kg/bid)或安慰剂。研究终点是蛋白尿,肾脏组织病理学,等离子体,肾脏损害的尿液生物标志物,和基因表达谱分析,以获得有关受runcaciguat影响的相关途径的信息。此外,比较了ZSF1大鼠肾脏和DKD患者肾脏样本中的氧化应激。在为期12周的治疗研究期间,肥胖ZSF1大鼠的肾功能显著下降,蛋白尿增加20倍,与瘦ZSF1大鼠相比。Runcaciguat剂量依赖性和显着减弱了ZSF1大鼠蛋白尿的发展,在研究结束时uPCR降低了-19%,-54%,在1、3和10mg/kg/bid时,为-70%,分别,与安慰剂治疗相比。此外,以HbA1C测量的平均血糖水平,甘油三酯,胆固醇增加了五倍,二十次,四次,分别,与瘦大鼠相比,肥胖ZSF1。在肥胖的ZSF1大鼠中,runcaciguat使HbA1c水平降低-8%,-34%,-76%,甘油三酯-42%,-55%,和-71%,胆固醇降低了16%,-17%,-34%,在1、3和10mg/kg/bid下,分别,与安慰剂相比。同时,runcaciguat也减轻了肾脏的重量,肾脏形态学损伤,以及肾脏损害的尿液和血浆生物标志物。有益的作用伴随着基因表达的变化,表明纤维化和炎症减少,并表明内皮稳定性得到改善。总之,在模拟CKD患者常见的合并症和氧化应激条件的DKD大鼠模型中,sGC激活剂runcaciguat显著阻止了肾功能下降.因此,runcaciguat代表CKD患者的一种有希望的治疗选择,这与最近的2期临床研究数据一致,其中runcaciguat在CKD患者中显示出有希望的疗效(NCT04507061)。
Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in
ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance.
ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcaciguat. Furthermore, oxidative stress was compared in the ZSF1 rat kidney with kidney samples from DKD patients. Within the duration of the 12-week treatment study, kidney function was significantly decreased in obese ZSF1 rats, indicated by a 20-fold increase in proteinuria, compared to lean
ZSF1 rats. Runcaciguat dose-dependently and significantly attenuated the development of proteinuria in
ZSF1 rats with reduced uPCR at the end of the study by -19%, -54%, and -70% at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo treatment. Additionally, average blood glucose levels measured as HbA1C, triglycerides, and cholesterol were increased by five times, twenty times, and four times, respectively, in obese ZSF1 compared to lean rats. In obese
ZSF1 rats, runcaciguat reduced HbA1c levels by -8%, -34%, and -76%, triglycerides by -42%, -55%, and -71%, and cholesterol by -16%, -17%, and -34%, at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo. Concomitantly, runcaciguat also reduced kidney weights, morphological kidney damage, and urinary and plasma biomarkers of kidney damage. Beneficial effects were accompanied by changes in gene expression that indicate reduced fibrosis and inflammation and suggest improved endothelial stabilization. In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061).