Abstract 86: Tumor Necrosis Factor-alpha Suppresses miR-29 and Up-regulates Fibrotic Genes in the Kidney

    loading  Checking for direct PDF access through Ovid


Tumor necrosis factor-alpha (TNF-a) is a pleiotropic inflammatory cytokine. Interstitial fibrosis is prominent in the Dahl salt-sensitive (SS) rat, including in the outer medullary region where thick ascending limbs (TALs) are abundant. We found previously that members of the miR-29 microRNA family, which have potent anti-fibrotic effects, were expressed at a lower level in the kidneys of SS rats. In the present study, we examined the role of TNF-a in the regulation of miR-29 and fibrotic genes in the kidney. RNA-seq analysis showed that SS rats fed a high salt diet had higher expression levels of TNF-a and TNFRSF1a which is one of its main receptors compared with a 0.4% salt diet group. Rat medullary thick ascending limb (mTAL) cells were treated with TNF-a at 25ng/ml for 24h or 48h. At 24h, TNF-a significantly decreased the abundance of miR-29b (to 57% ± 9% of control, n=14, p<0.05) and miR-29c (to 74% ± 6% of control, p<0.01) and significantly increased alpha-smooth muscle actin (a-SMA) by more than two fold and up-regulated extracellular matrix genes such as Col4a1 (to 161% ± 25% of control, n=10, p<0.05) and Col4a2 (to 172%± 18% of control, p<0.01). At 48h, TNF-a significantly suppressed miR-29a and again up-regulated a-SMA and Col4a2. Similarly, TNF-a suppressed miR-29 in primary cultures of human renal epithelial cells, an effect that was attenuated by inhibition of NF-kB. This study shows that TNF-a can suppress miR-29 and up-regulate fibrotic genes in renal epithelial cells including mTAL cells, which may play an important role in the development of renal tubulointerstitial injury in SS rats.

Related Topics

    loading  Loading Related Articles