Novel therapeutic strategy for renal fibrosis by targeting RNA-binding protein HuR

纤维化肾病是一个主要的卫生保健问题，因为它的普遍性和事实，现有的治疗方法只是减缓肾衰竭的进展。迫切需要新的创新疗法来减缓或阻止终末期肾病（ESRD）的进展。炎症是肾纤维化发生和发展的关键因素，这一点已经得到了很好的证实。然而，通过抑制单一的炎症因子是不可能充分减少肾脏炎症反应的。最近，人类抗原R （human antigen R, HuR）是一种控制mRNA稳定性和翻译的mRNA结合蛋白，已被确定为免疫反应和炎症的关键调节剂，通过调节细胞因子、炎症因子和对细胞功能和生存至关重要的蛋白质的mRNA稳定性。在多种肾脏疾病中观察到增强的肾HuR易位和激活。因此，靶向HuR可能为我们提供一种理想的方法来对抗肾脏炎症，从而控制肾脏疾病的进展。重要的是，我们最近发现了一种特异性的HuR抑制剂KH-3，它在实验性肾小球肾炎模型中显著改善肾功能，减少蛋白尿和肾纤维化。基于我们激动人心的数据，我们假设用KH-3抑制肾细胞中的HuR功能将抑制HuR靶向基因，这些基因对肾脏炎症和纤维化至关重要，从而导致慢性肾脏疾病（CKD）的缓解。为了验证我们的假设，我们将1)检测KH-3在两种主要促纤维化介质血管紧张素II和TGFβ1刺激的大鼠和人肾小球系膜细胞和小管细胞中的体外抗纤维化活性、靶点验证和作用机制；2)以PK/PD和MTD为指标，与正常大鼠比较，完善和优化肾炎大鼠体内KH-3的剂量/计划、给药方式和脱靶性；3)通过与肾小球硬化或小管间质纤维化相关的进行性CKD动物模型，评估KH-3在体内的治疗潜力。如果成功实施，我们的研究结果将为转化为临床环境提供重要的基础，为那些患有或有进展性CKD风险的患者提供更好的护理潜力。

Fibrotic renal disease represents a major health care problem because of its prevalence and the fact that available therapies merely slow the progression of renal failure. New innovative therapies to slow or stop the progression to the end-stage renal disease (ESRD) are urgently needed. It has been well established that inflammation is a key factor in the development and progression of renal fibrosis. However, it is impossible to reduce renal inflammatory reaction sufficiently by inhibiting a single inflammatory factor. Very recently, human antigen R (HuR), a mRNA-binding protein governing mRNA stability and translation, has been identified as a key modulator in immune response and inflammation through regulating mRNA stability of cytokines, inflammatory factors, and proteins critical for cell function and survival. Enhanced renal HuR translocation and activation has been observed in varied kidney diseases. Therefore, targeting HuR might provide us with an ideal way to against renal inflammation and thereby controlling renal disease progression. Importantly, we recently identified a specific HuR inhibitor, KH-3, which significantly ameliorated renal function and reduced proteinuria and renal fibrosis in the experimental glomerulonephritis model. Based on our exciting data, we hypothesize that inhibition of HuR function in renal cells with KH-3 will inhibit HuR-targeted genes that are critical for renal inflammation and fibrosis and thereby leading to remission of chronic kidney disease (CKD). To test our hypothesis, we will 1) examine the in vitro anti-fibrotic activity, target validation and mechanism(s) of action of KH-3 in rat and human renal glomerular mesangial cells and tubular cells stimulated by angiotensin II and TGFβ1, two major profibrotic mediators; 2) refine and optimize the dose/schedule, delivery method and off-targeting of KH-3 in vivo in rats with nephritis, compared with normal rats, based on PK/PD and MTD; and 3) Evaluate the therapeutic potential of KH-3 in vivo using animal models with progressive CKD related to glomerulosclerosis or tubulointerstitial fibrosis or both. Successfully carried out, our results will serve as an important basis for translation into the clinical setting with improved potential for patient care for those living with, or at the risk of, progressive CKD.