The HDAC2/SP1/miR-205 feedback loop contributes to tubular epithelial cell extracellular matrix production in diabetic kidney disease

Abstract

Extracellular matrix (ECM) accumulation is considered an important pathological feature of diabetic kidney disease (DKD). Histone deacetylase (HDAC) inhibitors protect against kidney injury. However, the potential mechanisms of HDACs in DKD are still largely unknown. Here, we describe a novel feedback loop composed of HDAC2 and miR-205 that regulates ECM production in tubular epithelial cells in individuals with DKD. We found that HDAC2 mRNA expression in peripheral blood was markedly higher in patients with DKD than in patients with diabetes. Nuclear HDAC2 protein expression was increased in TGFβ1-stimulated tubular epithelial cells and db/db mice. We also found that miR-205 was regulated by HDAC2 and downregulated in TGFβ1-treated HK2 cells and db/db mice. In addition, HDAC2 reduced histone H3K9 acetylation in the miR-205 promoter region to inhibit its promoter activity and subsequently suppressed miR-205 expression through an SP1-mediated pathway. Furthermore, miR-205 directly targeted HDAC2 and inhibited HDAC2 expression. Intriguingly, miR-205 also regulated its own transcription by inhibiting HDAC2 and increasing histone H3K9 acetylation in its promoter, forming a feedback regulatory loop. Additionally, the miR-205 agonist attenuated ECM production in HK2 cells and renal interstitial fibrosis in db/db mice. In conclusion, the HDAC2/SP1/miR-205 feedback loop may be crucial for the pathogenesis of DKD.

Butyrate suppresses atherosclerotic inflammation by regulating macrophages and polarization via GPR43/HDAC-miRNAs axis in ApoE−/− mice

“…MiRNAs are well-known for regulating gene expression at the post-transcriptional level by pairing with target sequences in the 3 0 untranslated region of mRNAs. The endogenously expressed miRNAs play important roles in many physiological and pathological processes [25]. MiR-205 was epigenetically regulated by HDAC2 through an Sp1-mediated pathway [25].…”

“…The endogenously expressed miRNAs play important roles in many physiological and pathological processes [25]. MiR-205 was epigenetically regulated by HDAC2 through an Sp1-mediated pathway [25]. MiR-7a/b protected against cardiac remodeling and hypoxia-induced injury in H9c2 cardiomyoblasts involving Sp1 and PARP-1 [26].…”

Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis

“…At the same time, HDAC2 reduces histone H3K9 acetylation in the miR-205 promoter and inhibits its expression through an SP1-mediated pathway. miR-205 also regulates its own transcription by inhibiting HDAC2 and increasing histone H3K9 acetylation in its promoter, forming a feedback regulatory loop [ 138 ]. Similarly, miR-376a and HDAC9 form a regulatory circuitry in hepatocellular carcinoma: HDAC9, which is a direct target of miR-376a, also increases the expression of miR-376a by upregulating the global histone H3K18 acetylation level [ 141 ].…”

SNHG16/miR‐205/HDAC5 is involved in the progression of renal fibrosis

“…Previously study has been suggested that miR‐205 can relieve the renal fibrosis in mice. [ 11 ] By bioinformatic analysis, we discovered that lncRNA SNHG16 had the mutual binding sites of miR‐205. Based on this, this work established a unilateral ureteral obstruction (UUO)‐induced mouse renal fibrosis model, and explored whether lncRNA SNHG16 regulated the progression of renal fibrosis by targeting miR‐205.…”