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Sci Transl Med. 2018 Oct 10;10(462). pii: eaat2039. doi: 10.1126/scitranslmed.aat2039.

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

Author information

1
Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou 510515, China.
2
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
3
Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou 510515, China. ffhouguangzhou@163.com.

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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