Chronic interstitial dysregulation of tissue homeostasis is often accompanied by fibrotic alterations. The reasons for unbalanced matrix homeostasis seem to involve altered action of regulatory cytokines or miRNAs. We used the fibrogenic nephrotoxin ochratoxin A (OTA) and other cell stressors to investigate the role and expression of miR-29b, which has anti-fibrotic effects by regulating extracellular matrix genes, and of a transcript of Wnt1 inducible signaling pathway protein 1 (WISP1) in the onset of fibrotic events in the kidney.

In renal epithelial cells OTA and PMA strongly induce the expression of a non-coding RNA derived from WISP1 gene, which we named lncWISP1. lncWISP1 is a truncated version of WISP1 that consists of only a part of the last exon which includes the 3´UTR and involves one binding site for miR-29b. Binding of miR-29b to the corresponding seed region in lncWISP1 was confirmed by luciferase assay. Moreover, we found that OTA exposure snatches away miR-29b most probably as a result of the strong lncWISP1 induction which acts as a miRNA sponge. An increase of cellular miR-29b levels using mimics led to a decreased collagen I, III and IV gene and protein expression. In contrast, OTA enhanced the collagen I, III and IV amount in the media. This effect was abolished when cellular miR-29b was clamped at a high level using mimics.

These results demonstrate that the stress-induced expression of an endogenous miR-29b sponge (lncWISP1) can promote the deposition of extracellular matrix in renal epithelial cells and thereby may participate in fibrotic modifications.

Figure 1