Transforming growth factor β1 (TGF‐β1) enhances expression of pro‐fibrotic genes through a novel miRNA‐mediated cascade in renal mesangial cells (LB208)

Abstract

Increased TGF‐β1 expression in glomerular mesangial cells (MC) augments extracellular matrix accumulation, hypertrophy and pro‐fibrotic genes during the progression of diabetic nephropathy (DN), a debilitating renal complication of diabetes. microRNAs (miRNAs) play key roles in the pathogenesis of DN by modulating the actions of TGF‐β1 to enhance the expression of pro‐fibrotic genes like collagen. In this study, we found a significant decrease in the expression of key members of the miR‐130 and miR‐30 families in mouse MC (MMC) treated with TGF‐β1. In parallel there was a decrease in host genes 2610318N02RIK (RIK, miR‐130b host gene) and NF‐YC (miR‐30e* host gene), suggesting host gene‐dependent expression of these miRNAs. TGF‐β receptor1 (TGF‐βR1), was identified as a target of miR‐130b. Interestingly, the RIK promoter contains three NF‐YC binding sites and was regulated by NF‐YC, a potential target of miR‐216a which was also up‐regulated by TGF‐β1. Therefore, a novel cascade, ↑TGF‐β1>↑miR‐216a>↓NF‐YC>↓RIK (↓miR‐130b) may up‐regulate TGF‐βR1 to augment expression of TGF‐β1 target fibrotic genes. miR‐130 and miR‐30e* were down‐regulated, whereas TGF‐βR1, as well as the pro‐fibrotic genes COLIVa1, COLXIIa1, CTGF and PAI‐1 were up‐regulated by TGF‐β1 in MMC and in the glomeruli of streptozotocin injected diabetic mice, supporting in vivo relevance. Together, these results demonstrate a novel miRNA‐ and their host gene‐mediated cascade initiated by TGF‐β1 which results in the up‐regulation of pro‐fibrotic factors such as TGF‐βR1 and collagens associated with the progression of DN.Grant Funding Source: Supported by NIH R01 DK081705 and ADA 7‐10‐MI‐07