Identification of Novel Long Noncoding RNAs Associated with TGF-β/Smad3-Mediated Renal Inflammation and Fibrosis by RNA Sequencing

• DOI: 10.1016/j.ajpath.2013.10.007
• Publication Date: 2013-11-21T06:41:04Z
• Authors: Qin Zhou; Arthur C.K. Chung; Xiao R. Huang; Yuan Dong; Xueqing Yu; Hui Y. Lan
• Keywords: Inflammation; Male; Mice, Knockout; 0303 health sciences; Binding Sites; Base Sequence; Sequence Analysis, RNA; Molecular Sequence Data; Kidney; Fibrosis; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Gene Ontology; Glomerulonephritis; Gene Expression Regulation; Animals; Female; RNA, Long Noncoding; Smad3 Protein; Protein Binding; Signal Transduction

We have previously shown that transforming growth factor-β/Smad3-dependent miRNAs play a critical role in renal inflammation and fibrosis. However, off-target effects of miRNAs limit their therapeutic application. Recently, emerging roles of long noncoding RNAs (lncRNAs) in diseases have been recognized. In this study, we used high-throughput RNA sequencing to identify the Smad3-dependent lncRNAs related to renal inflammation and fibrosis in Smad3 knockout mouse models of unilateral ureteral obstructive nephropathy and immunologically induced anti-glomerular basement membrane glomerulonephritis. Compared with wild-type mice, 151 lncRNAs in the unilateral ureteral obstructive nephropathy kidney and 413 lncRNAs in kidneys with anti-glomerular basement membrane glomerulonephritis were significantly altered in Smad3 knockout mice. Among them, 21 common lncRNAs were up-regulated in wild-type, but down-regulated in Smad3 knockout, kidneys in both disease models in which progressive renal inflammation and fibrosis were abolished when the Smad3 gene was deleted or suppressed. Real-time PCR confirmed these findings and revealed the functional link between Smad3-dependent lncRNAs np_5318/np_17856 and progressive kidney injury. Results demonstrate that the identification and characterization of functional lncRNAs associated with kidney disease may represent a promising research direction into renal disorder and may lead to the development of new lncRNA therapies for kidney diseases.