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

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 (<i>lnc-TSI</i>). <i>Lnc-TSI</i> was transcriptionally regulated by Smad3 and specifically inhibited TGF-β-induced Smad3 phosphorylation and downstream profibrotic gene expression. <i>Lnc-TSI</i> 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 <i>lnc-TSI</i> 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), <i>lnc-TSI</i> renal expression negatively correlated with the renal fibrosis index (<i>r</i> = -0.56, <i>P</i> < 0.001) after adjusting for cofounders. In a longitudinal study, 32 IgAN patients with low expression of renal <i>lnc-TSI</i> 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 <i>lnc-TSI</i> reduced renal fibrogenesis through negative regulation of the TGF-β/Smad pathway.