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

Addtime:2018/10/15Hits:101Source:Center Office

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.

Detail Information
Wang P, Luo ML, Song E, Zhou ZM, Ma TT, Wang J, Jia N, Wang GB, Nie S, Liu YH, Hou FF. Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway. Sci. Transl. Med. 10, eaat2039 (2018)

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