In:
Journal of Molecular Medicine, Springer Science and Business Media LLC, Vol. 98, No. 4 ( 2020-04), p. 527-540
Abstract:
Progressive tubulointerstitial fibrosis is the common final outcome for all kidney diseases evolving into chronic kidney disease (CKD), whereas molecular mechanisms driving fibrogenesis remain elusive. Retinoic acid-inducible gene-I (RIG-I), an intracellular pattern recognition receptor, is originally identified participating in immune response by recognizing virus RNA. Here, we revealed for the first time that RIG-I was induced in unilateral ureteral obstruction (UUO) and folic acid (FA) renal fibrosis models and moderate-degree renal fibrosis patients. Besides, we found RIG-I was mainly located in renal tubular epithelial cells and promoted the production and release of inflammatory cytokines, such as interleukin (IL)-1β and IL-6 through activation of NF-κB. Inflammatory cytokines released by tubular epithelial cells activated c-Myc-mediated TGF-β/Smad signaling in fibroblasts, which in turn aggravated interstitial fibrosis by promoting fibroblast activation and production of extracellular matrix components (ECM). Deficiency of RIG-I attenuated renal fibrosis by the regulation of inflammatory responses, c-Myc expression, and fibroblast activation. Besides, gene silencing of RIG-I reduced inflammatory cytokines in cultured tubular epithelial cells treated with Angiotensin II. Knockdown of c-Myc or c-Myc inhibitor blocked IL-1β-induced fibroblast activation. Collectively, our study demonstrates that RIG-I plays a significant role in the progress of renal fibrosis via regulating c-Myc-mediated fibroblast activation. Key messages • RIG-I was constantly elevated in kidneys from renal fibrotic mice. • RIG-I facilitated inflammatory cytokine production in tubular epithelial cells. • RIG-I aggravated renal fibrosis via c-Myc-mediated TGF-β/Smad activation.
Type of Medium:
Online Resource
ISSN:
0946-2716
,
1432-1440
DOI:
10.1007/s00109-020-01879-x
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
1462132-0
SSG:
12
Bookmarklink