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

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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.