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Erschienen in:
01.08.2014 | Article
MiR-135a promotes renal fibrosis in diabetic nephropathy by regulating TRPC1
Erschienen in: Diabetologia | Ausgabe 8/2014
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Aims/hypothesis
The contribution of aberrantly expressed microRNAs (miRNAs) to diabetic nephropathy in vivo is poorly understood.
Methods
Integrated comparative miRNA array profiling was used to examine the expression of serum miRNAs in patients with diabetic nephropathy. The abundance of miRNA-135a (miR-135a) was measured by real-time quantitative PCR in the serum and kidney tissues of patients with diabetic nephropathy. The luciferase assay combined with mutation and immunoblotting was used to screen and verify the bioinformatically predicted miRNAs. Ca2+ entry or intracellular Ca2+ ([Ca2+]i) was performed by imaging Fura-2/AM-loaded cells using a fluorescence microscopy system. The role of miR-135a in vivo was explored with locked nucleic acid antisense oligonucleotides.
Results
MiR-135a was markedly upregulated in serum and renal tissue from patients with diabetic nephropathy, as well from db/db mice, and this was associated with the development of microalbuminuria and renal fibrosis. Furthermore, we identified transient receptor potential cation channel, subfamily C, member 1 (TRPC1) as a target of miR-135a during renal injury. We demonstrated that overexpression of TRPC1 was able to reverse the pathological effects of miR-135a on promoting proliferation of mesangial cells and increasing synthesis of extracellular matrix proteins. Moreover, miR-135a attenuated store depletion-induced Ca2+ entry into cells by regulating TRPC1. Importantly, knockdown of miR-135a in diabetic kidneys restored levels of TRPC1 and reduced synthesis of fibronectin and collagen I in vivo. Suppressing TRPC1 levels to prevent Ca2+ entry into cells may be a mechanism whereby miR-135a promotes renal fibrosis in diabetic kidney injury.
Conclusions/interpretation
These findings suggest an important role for miR-135a in renal fibrosis and inhibition of miR-135a might be an effective therapy for diabetic nephropathy.