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

纤维化肾病代表了一个主要的卫生保健问题，因为它的流行和可用的疗法仅仅减缓肾衰竭的进展的事实。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。然而，不可能通过抑制单一的炎症因子来充分降低肾脏炎症反应。最近，人类抗原R（HuR），一种控制mRNA稳定性和翻译的mRNA结合蛋白，已被鉴定为通过调节细胞因子、炎性因子和对细胞功能和存活至关重要的蛋白质的mRNA稳定性而在免疫应答和炎症中的关键调节剂。在各种肾脏疾病中已经观察到增强的肾脏HuR易位和活化。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HuR抑制剂KH-3，它在实验性肾小球肾炎模型中显著改善了肾功能，减少了蛋白尿和肾纤维化。基于我们令人兴奋的数据，我们假设用KH-3抑制肾细胞中的HuR功能将抑制对肾脏炎症和纤维化至关重要的HuR靶向基因，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在大鼠和人肾小球系膜细胞和肾小管细胞中的体外抗纤维化活性、靶点验证和作用机制，所述肾小球系膜细胞和肾小管细胞由两种主要的促纤维化介质血管紧张素II和TGFβ1刺激; 2）改进和优化KH-3在肾炎大鼠体内的剂量/时间表、递送方法和脱靶，与正常大鼠相比，基于PK/PD和MTD;和3）使用患有与肾小球硬化或肾小管间质纤维化或两者相关的进行性CKD的动物模型评估KH-3的体内治疗潜力。成功地进行，我们的结果将作为转化为临床环境的重要基础，为那些患有或有进展性CKD风险的患者提供更好的患者护理。

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.