tiRNA-Gly-GCC-002 promotes epithelial-mesenchymal transition and fibrosis in lupus nephritis via FKBP5-mediated activation of Smad.

BACKGROUND AND PURPOSE: Renal interstitial fibrosis is a frequent pathological manifestation of lupus nephritis (LN). tRNA halves (tiRNAs) are acquired from tRNA-derived small non-coding RNAs (sncRNAs) and are associated with fibrosis. Our previous study indicated enhanced tiRNA-Gly-GCC-002 (tiRNA002) levels in kidneys were positively related to LN-related fibrosis. However, the precise molecular mechanism remains unclear.

EXPERIMENTAL APPROACH: The mimic and agomiR of tiRNA002 were introduced into tubular epithelial cells (TECs) and MRL/lpr mice by transfection. The levels of gene and protein expressions were quantified using real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assays.

KEY

RESULTS

In TECs treated with LN serum, as well as in the kidneys of MRL/lpr mice, high levels of tiRNA002 directly influenced the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Furthermore, tiRNA002 overexpression promoted EMT in TECs and accelerated renal interstitial fibrosis in MRL/lpr mice via Smad signalling. The target gene of tiRNA002, FKBP prolyl isomerase 5 (FKBP5), improved Smad signalling by interacting with phosphorylated Smad2/3. Silencing FKBP5 alleviated LN serum- or tiRNA002-mimic-induced EMT in TECs. In addition, FKBP5 overexpression reversed the tiRNA002 knockdown-mediated reduction of EMT and ECM accumulation.

CONCLUSIONS AND IMPLICATIONS: These findings indicated that tiRNA002 is markedly increased in LN, which facilitates renal fibrosis by promoting EMT via FKBP5-mediated Smad signalling. Therefore, targeting tiRNA002 may be an innovative approach to treat renal interstitial fibrosis in LN.