Abstract
In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qkv) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKIFL/FL;LysM-Cre mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qkv and QKIFL/FL;LysM-Cre mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKIFL/FL;LysM-Cre mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.
Highlights
IntroductionThe QUAKING RNA-binding proteins belong to the family of KH-type RNA-binding proteins [1,2]
The QUAKING RNA-binding proteins belong to the family of KH-type RNA-binding proteins [1,2].The qkI gene expresses three major alternatively spliced mRNAs encodingQKI-5, QKI-6 and QKI-7 that differ in their C-terminal 30 amino acids [3]
We investigated whether reduced QKI expression in monocytes/macrophages offered protection against kidney injury induced by urethral obstruction (UUO)
Summary
The QUAKING RNA-binding proteins belong to the family of KH-type RNA-binding proteins [1,2]. QKI-5, QKI-6 and QKI-7 that differ in their C-terminal 30 amino acids [3]. The QKI-5 isoform contains a unique stretch of basic amino acids at its C-terminus that functions as a nuclear localization signal [4]. QKI belongs to the heteronuclear ribonucleoprotein particle K (hnRNP K) homology (KH) domain family of RNA-binding proteins. QKI binds specific RNA sequences with high affinity termed a QKI. The QKI isoforms dynamically alter the post-transcriptional landscape in many cell types including oligodendrocytes, endothelial cells, (smooth) muscle cells, monocytes and macrophages by regulating RNA processing including pre-mRNA splicing [3,6,7,8]
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