Abstract
PurposeThis study aimed to evaluate the mechanism by which miR-29c expression in fibroblasts regulates renal interstitial fibrosis.MethodsWe stimulated NRK-49F cells with TGF-β1 to mimic the effects of fibrosis in vitro, while unilateral ureteral obstruction (UUO) was performed to obstruct the mid-ureter in mice. MiR-29c mimic or miR-29c inhibitor was used to mediate genes expressions in vitro. The recombinant adeno associated virus (rAAV) vectors carrying a FSP1 promoter that encodes miR-29c precursor or miR-29c inhibitor was used to mediate genes expressions in vivo, and a flank incision was made to expose the left kidney of each animal.ResultsIn the present study, TGF-β1 was demonstrated to regulate miR-29c expression through Wnt/β-catenin signaling. In contrast, miR-29c appears to inhibit the Wnt/β-catenin pathway by suppressing TPM1 expression. As suggested by this feedback mechanism, miR-29c may be a key fibrosis-related microRNA expressed by fibroblasts in TGF-β1/Wnt/β-catenin-driven renal fibrosis, and manipulation of miR-29c action may accordingly offer a potential therapeutic pathway for renal fibrosis treatment.ConclusionMiR-29c expression was downregulated in UUO mouse kidneys as well as TGF-β1-treated NRK-49F cells, which thus inhibits myofibroblast formation via targeting of TPM1. Additionally, the production of extracellular matrix (ECM) in renal fibroblasts appears to be controlled by the reciprocal regulation of miR-29c action and the Wnt/β-catenin pathway.
Highlights
Renal interstitial fibrosis – characterized by the accumulation of extracellular matrix (ECM), renal fibroblast and myofibroblast along with inflammation cell infiltration into renal tubular interstitial fluids and structural deterioration – often promotes the progression of chronic kidney disease (CKD) to its end-stage (Eddy, 1996; Satoh et al, 2001; Taneda et al, 2003)
We found that miR-29c exhibits higher expression in NRK-49F than in NRK-52E (Supplementary Figure S1A)
RT-PCR confirmed that transforming growth factor (TGF)-β1 treatment downregulated miR-29c expression in a dose- and time-dependent manner relative to the control, troughing at 12 h with an optimal dose of 10 ng/mL (Figures 1A,B)
Summary
Renal interstitial fibrosis – characterized by the accumulation of extracellular matrix (ECM), renal fibroblast and myofibroblast along with inflammation cell infiltration into renal tubular interstitial fluids and structural deterioration – often promotes the progression of chronic kidney disease (CKD) to its end-stage (Eddy, 1996; Satoh et al, 2001; Taneda et al, 2003). Because the expression of transforming growth factor (TGF)-β1 is upregulated in all types of CKD, in both experimental models and clinical settings, it is likely the most potent inducer of fibrosis. TGF-β1 has been extensively shown to play a vital role in promoting the production of collagen, which can result in kidney dysfunction during the fibrogenic phase of renal fibrosis (Roberts, 1998; Wang et al, 2005; Lan and Chung, 2011). The various mechanisms that regulate kidney fibrosis and fibroblast activation have not yet been determined
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
