Research ArticleFibrosis

Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway

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Science Translational Medicine  10 Oct 2018:
Vol. 10, Issue 462, eaat2039
DOI: 10.1126/scitranslmed.aat2039

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A target for renal fibrosis

Transforming growth factor–β (TGF-β) is a known regulator of fibrosis but has remained difficult to target. Wang et al. identified a kidney-specific long noncoding RNA, lnc-TSI, that inhibited Smad3 activation and downstream profibrogenic gene expression in human tubular epithelial cells (TECs). Ectopic lnc-TSI expression in mouse TECs confirmed inhibition of TGF-β signaling, and delivery of lnc-TSI in unilateral ureteral obstruction and ischemic reperfusion injury–induced fibrosis models resulted in reduced renal fibrogenesis. Expression of lnc-TSI negatively correlated with fibrosis and renal failure in IgA nephropathy patients, raising the possibility that the lncRNA could be a potential therapeutic target.

Abstract

Transforming growth factor–β (TGF-β) is a well-established central mediator of renal fibrosis, a common outcome of almost all progressive chronic kidney diseases. Here, we identified a poorly conserved and kidney-enriched long noncoding RNA in TGF-β1–stimulated human tubular epithelial cells and fibrotic kidneys, which we termed TGF-β/Smad3-interacting long noncoding RNA (lnc-TSI). Lnc-TSI was transcriptionally regulated by Smad3 and specifically inhibited TGF-β–induced Smad3 phosphorylation and downstream profibrotic gene expression. Lnc-TSI acted by binding with the MH2 domain of Smad3, blocking the interaction of Smad3 with TGF-β receptor I independent of Smad7. Delivery of human lnc-TSI into unilateral ureteral obstruction (UUO) mice, a well-established model of renal fibrosis, inhibited phosphorylation of Smad3 in the kidney and attenuated renal fibrosis. In a cohort of 58 patients with biopsy-confirmed IgA nephropathy (IgAN), lnc-TSI renal expression negatively correlated with the renal fibrosis index (r = −0.56, P < 0.001) after adjusting for cofounders. In a longitudinal study, 32 IgAN patients with low expression of renal lnc-TSI at initial biopsy had more pronounced increases in their renal fibrosis index and experienced stronger declines in renal function at repeat biopsy at a mean of 48 months of follow-up. These data suggest that lnc-TSI reduced renal fibrogenesis through negative regulation of the TGF-β/Smad pathway.

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