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TGF-? Mediates Renal Fibrosis via the Smad3-Erbb4-IR Long Noncoding RNA Axis.

ABSTRACT: Transforming growth factor ? (TGF-?)/Smad3 signaling plays a role in tissue fibrosis. We report here that Erbb4-IR is a novel long non-coding RNA (lncRNA) responsible for TGF-?/Smad3-mediated renal fibrosis and is a specific therapeutic target for chronic kidney disease. Erbb4-IR was induced by TGF-?1 via a Smad3-dependent mechanism and was highly upregulated in the fibrotic kidney of mouse unilateral ureteral obstructive nephropathy (UUO). Silencing Erbb4-IR blocked TGF-?1-induced collagen I and alpha-smooth muscle actin (?-SMA) expressions in vitro and effectively attenuated renal fibrosis in the UUO kidney by blocking TGF-?/Smad3 signaling. Mechanistic studies revealed that Smad7, a downstream negative regulator of TGF-?/Smad signaling, is a target gene of Erbb4-IR because a binding site of Erbb4-IR was found on the 3' UTR of Smad7 gene. Mutation of this binding site prevented the suppressive effect of Erbb4-IR on the Smad7 reporter activity; in contrast, overexpression of Erbb4-IR largely inhibited Smad7 but increased collagen I and ?-SMA transcriptions. Thus, kidney-specific silencing of Erbb4-IR upregulated renal Smad7 and thus blocked TGF-?/Smad3-mediated renal fibrosis in vivo and in vitro. In conclusion, the present study identified that Erbb4-IR is a novel lncRNA responsible for TGF-?/Smad3-mediated renal fibrosis by downregulating Smad7. Targeting Erbb4-IR may represent a precise therapeutic strategy for progressive renal fibrosis.


PROVIDER: S-EPMC5763082 | BioStudies | 2018-01-01T00:00:00Z

REPOSITORIES: biostudies

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