New findings! Egr1 is a target for the treatment of fibrotic nephropathy

Posted by Caroline on April 26th, 2022

Epigenetic modifications play a crucial role in various biological processes and diseases, and DNA methylation is an important mechanism of epigenetic inheritance. DNA methyltransferases (DNMT1, DNMT3a, and Dnmt3b) are involved in the generation and maintenance of the epigenome.

Specifically, DNMT3a and Dnmt3b are responsible for establishing DNA methylation, whereas DNMT1 maintains methylation. A recent study showed that inhibition of DNMT1 could improve renal fibrosis. Therefore, the regulation of DNA methylation levels has become the focus of renal fibrosis research.

Methyl CpG binding domain protein 2 (Mbd2) may be involved in the regulation of gene transcriptional activity and plays a key role in a variety of diseases. However, the role of tubular Mbd2 in renal fibrosis is unknown. Early growth response protein 1 (Egr1) is a member of the immediate-early response gene family and plays an important role in renal fibrosis induced by a variety of growth factors. Therefore, the regulatory role and mechanism of Mbd2 in Egr1 expression are unknown.

Recently, researchers from Central South University published an article entitled \"Genetic or siRNA inhibition of MBD2 attenuates the UO- and I/R-induced renal fibrosis via downregulation of EGR1\" in the journal Molecular Therapy: Nucleic Acids. This study demonstrates that inhibition of Mbd2 reduces renal fibrosis by downregulating Egr1, which may be a target for the treatment of fibrotic nephropathy.

In this study, the investigators found that Mbd2 mediated transforming growth factor-β1-induced extracellular matrix (ECM) production by mouse tubule (BUMPT) cells and up-regulated Egr1 expression to promote ECM production by mouse embryonic NIH3T3 fibroblasts. CHIP analysis indicated that Mbd2 physically interacts with the promoter region of the CpG island of the Egr1 gene and then activates its expression by inducing hypomethylation of the promoter region.

In vivo, PT-Mbd2-knockdown attenuated tubulointerstitial fibrosis in response to unilateral ureteral obstruction (UUO) by downregulating Egr1 expression, as indicated by downregulation of fibronectin (FN), collagen I and IV, α-SMA, and Egr1. Alternatively, injection of Mbd2-siRNA attenuates UUO- and I/R-induced renal fibrosis. Biopsies from patients with obstructive nephropathy (OB) confirmed these molecular changes.

In summary, the present study is the first report on tubular Mbd2 as an inducer of renal fibrosis. In addition, investigators have described a novel mechanism by which Mbd2 induces Egr1 expression. These changes lead to an increase in renal fibrosis by inducing hypomethylation of the promoter. Therefore, the present study suggests that tubular Mbd2 may be an attractive target for the treatment of renal fibrosis.