微肽MRIF在促进儿童急性肾损伤向慢性肾脏病转归中的作用与机制研究

Chronic kidney disease (CKD) is a major problem around the world. There is increasing evidence that acute kidney injury (AKI) which was believed benign is the final common pathway leading to CKD and end-stage renal disease (ESRD). Inflammation and fibrogenesis are the two major determinants of the progression from AKI to CKD. Currently we lack the specific treatments to halt AKI to CKD, making this unmet clinical need. We identified c-Jun N-terminal kinase (JNK)/c-Jun and TGF-β1/Smad3 signaling pathways were co-activated in AKI mouse model and blockading both JNK/c-Jun and TGF-β1/Smads signaling pathways achieved better protection from AKI induced progressive renal tubulointertstitial damage than single blockade. Recently studies demonstrated that small open reading frame (smORF) is a novel active regulator in the inflammatory and fibrotic networks. Futher, we have identified a group of non-coding RNAs (ncRNA) relevant with both JNK/c-Jun and TGF-β1/Smads signaling pathways through performing a RNA-sequencing analysis and bioinformatics screen of ncRNA expressed in biopsy tissue from patients with CKD after AKI. Follow-up analysis identified a candidate smORF encoded by one of the ncRNA could regulates fibrosis in human renal tubular epithelial cells. Based on our considerable preliminary data, we have named this molecule micro-peptide Regulator of Inflammation and Fibrosis (MRIF). Our MRIF deficient mice were protected from renal inflammation and interstitial fibrosis in model of unilateral ureteral obstruction (UUO). Finally our in vitro study demonstrated that MRIF bridges ATF2 and CDK9. Based on our preliminary data, we hypothesize that MRIF plays a novel role in the development and progression of AKI to CKD by regulating both JNK/c-Jun and TGF-β1/Smads signaling pathways. The functional role of MRIF will be determined by MRIF knockout mice in our recently established I/R mouse model. We will also perform mechanistic studies to explore how MRIF integrates JNK/c-Jun and TGF-β1/Smad3 signalling pathways to promote the transition of AKI to CKD. This study presents a novel mechanism for the progression of AKI to CKD and provides a potential new therapeutic target for CKD.

急性肾损伤（AKI）后持续的炎症反应和肾间质纤维化是其进展至慢性肾脏病（CKD）的重要危险因素，但具体机制不明，治疗手段有限。我们前期发现：促炎、促纤维化的JNK和TGF-β1信号通路共同促进AKI小鼠肾脏纤维化的发生发展。最近发现：小开放阅读框（smORF）编码的微肽可能在炎症和纤维化信号网络中发挥重要作用。我们从AKI进展至CKD的患儿肾组织中筛选出特异性表达的、并与JNK和TGF-β1通路相关的微肽MRIF。敲除MRIF基因可减轻UUO小鼠肾间质炎症和纤维化；且MRIF可促进JNK和TGF-β1下游分子ATF2和CDK9结合。据此推测：MRIF可能通过促进JNK和TGF-β1信号通路的对话和交联从而促进AKI向CKD进展。本项目拟通过MRIF基因敲除小鼠建立AKI模型，通过体内外实验探讨MRIF促进AKI向CKD转归的作用及分子机制，为改善AKI预后、早期防治CKD提供新思路和新靶点

急性肾损伤(AKI)后持续的炎症反应和肾间质纤维化是其进展至慢性肾脏病(CKD)的重要危险因素，目前尚无特异性有效延缓其进展的手段。近年研究发现非编码RNA存在部分小开放阅读框(smORF)，其编码的微肽可能是炎症和纤维化信号网络中的重要作用调控分子，在儿童AKI向CKD转归中的作用值得研究。我们前期从AKI进展至CKD的患儿肾组织中筛选出特异性表达的、并与JNK和TGF-β1通路相关的微肽MRIF，推测MRIF可能通过促进JNK和TGF-β1信号通路的对话和交联从而促进AKI向CKD进展。本项目通过构建MRIF基因敲除小鼠，改良AKI模型，证明了敲除MRIF基因可减轻小鼠肾脏纤维化、保护肾功能。进一步合成MRIF特异性阻断剂LNA-MRIF及siRNA，通过体内、外实验证实予 LNA-MRIF干预可减缓AKI小鼠疾病进展，且联合LNA-MRIF与JNK、Smad3特异性阻断剂干预可进一步减轻AKI小鼠肾脏纤维化、保护肾功能。为改善AKI预后、早期防治CKD提供新思路和新靶点。

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