Journal
DIABETOLOGIA
Volume 56, Issue 3, Pages 663-674Publisher
SPRINGER
DOI: 10.1007/s00125-012-2804-x
Keywords
Diabetic nephropathy; MicroRNA-21; TGF-beta signalling; Smad7
Categories
Funding
- Research Grant Council of Hong Kong [RGC GRF 468711, 469110, 768409, CUHK5/CRF/09, GRF 464010, 463612, 763908, 764109]
- Focused Investment Scheme B [1902061]
- Chinese University of Hong Kong [2041656, 2041735]
- Hong Kong Society of Nephrology [6903213]
- National Natural Science Foundation of China (General Program) [81170681]
- Major State Basic Research Development Program of China (973 program) [2012CB517700]
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As microRNA-21 (miR-21) plays a pathological role in fibrosis, we hypothesised that it may be a therapeutic target for diabetic nephropathy. Abundance of miR-21 was examined in diabetic kidneys from db/db mice. The therapeutic potential of miR-21 in diabetic kidney injury was examined in db/db mice by an ultrasound-microbubble-mediated miR-21 small hairpin RNA transfer. In addition, the role and mechanisms of miR-21 in diabetic renal injury were examined in vitro under diabetic conditions in rat mesangial and tubular epithelial cell lines by overexpressing or downregulating miR-21. In db/db mice, a mouse model of type 2 diabetes, renal miR-21 at age 20 weeks was increased twofold compared with db/m (+) mice at the same age, and this increase was associated with the development of microalbuminuria and renal fibrosis and inflammation. More importantly, gene transfer of miR-21 knockdown plasmids into the diabetic kidneys of db/db mice at age 10 weeks significantly ameliorated microalbuminuria and renal fibrosis and inflammation at age 20 weeks, revealing a therapeutic potential for diabetic nephropathy by targeting miR-21. Overexpression of miR-21 in kidney cells enhanced, but knockdown of miR-21 suppressed, high-glucose-induced production of fibrotic and inflammatory markers. Targeting Smad7 may be a mechanism by which miR-21 regulates renal injury because knockdown of renal miR-21 restored Smad7 levels and suppressed activation of the TGF-beta and NF-kappa B signalling pathways. Inhibition of miR-21 might be an effective therapy for diabetic nephropathy.
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