Organ-specific microRNAs have essential roles in maintaining normal organ function. However， the microRNA profile of the kidney and the role of microRNAs in modulating renal function remain undefined. We performed an unbiased assessment of the genome-wide microRNA expression profile in 14 mouse organs using Solexa deep sequencing and found that microRNA-196a (miR-196a) and miR-196b are selectively expressed in kidney， with 74.37% of mouse total miR-196a and 73.19% of mouse total miR-196b distributed in the kidneys. We confirmed the predominant expression of miR-196a in mouse and human kidney， particularly in the glomeruli and tubular epithelium， by quantitative RT-PCR and in situ hybridization assays. D... More
Organ-specific microRNAs have essential roles in maintaining normal organ function. However， the microRNA profile of the kidney and the role of microRNAs in modulating renal function remain undefined. We performed an unbiased assessment of the genome-wide microRNA expression profile in 14 mouse organs using Solexa deep sequencing and found that microRNA-196a (miR-196a) and miR-196b are selectively expressed in kidney， with 74.37% of mouse total miR-196a and 73.19% of mouse total miR-196b distributed in the kidneys. We confirmed the predominant expression of miR-196a in mouse and human kidney， particularly in the glomeruli and tubular epithelium， by quantitative RT-PCR and in situ hybridization assays. During unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis， renal miR-196a levels rapidly decreased. Elevation of renal miR-196a expression by hydrodynamic-based delivery of a miR-196a-expressing plasmid before or shortly after UUO significantly downregulated profibrotic proteins， including collagen 1 and α-smooth muscle actin， and mitigated UUO-induced renal fibrosis. In contrast， depletion of renal miR-196a by miR-196a antagomirs substantially aggravated UUO-induced renal fibrosis. Mechanistic studies further identified transforming growth factor beta receptor II (TGFβR2) as a common target of miR-196a and miR-196b. Decreasing miR-196a expression in human HK2 cells strongly activated TGF-β-Smad signaling and cell fibrosis; whereas increasing miR-196a levels in mouse primary cultured tubular epithelial cells inhibited TGF-β-Smad signaling. In the UUO model， miR-196a silenced TGF-β-Smad signaling， decreased the expression of collagen 1 and α-smooth muscle actin， and attenuated renal fibrosis. Our findings suggest that elevating renal miR-196a levels may be a novel therapeutic strategy for treating renal fibrosis.
