Blockade of Enhancer of Zeste Homolog 2 alleviates renal injury associated with hyperuricemia.

In this study, we demonstrated that blockade of EZH2 with 3-DZNeP, a selective EZH2 inhibitor, or silencing of EZH2 with siRNA inhibited uric acid-induced renal fibroblast activation and phosphorylation of Smad3, epidermal growth factor receptor (EGFR) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in cultured renal fibroblasts. Inhibition of EZH2 also suppressed proliferation of renal fibroblasts and epithelial-mesenchymal transition (EMT) of tubular cells. In a mouse model of renal injury induced by hyperuricemia, EZH2 and H3K27me3 expression levels were enhanced, which was coincident with renal damage and increased expression of lipocalin-2 and cleaved caspase-3. Inhibition of EZH2 with 3-DZNeP blocked all these responses. Furthermore, 3-DZNeP treatment decreased the level of serum uric acid and xanthine oxidase (XOD) activity, alleviated renal interstitial fibrosis, inhibited activation of TGF-β/Smad3, EGFR/ERK1/2 and nuclear factor-κB (NF-κB) signaling pathways, as well as reduced expression of multiple chemokines/cytokines. Collectively, EZH2 inhibition can reduce the level of serum uric acid and alleviate renal injury and fibrosis through a mechanism associated with inhibition of multiple signaling pathways. Targeting EZH2 may be a novel strategy for the treatment of hyperuricemia induced CKD. PMID: 30566000 [PubMed - as supplied by publisher]
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research