DNA hypomethylation of Syk induces oxidative stress and apoptosis via the PKCβ/P66shc signaling pathway in diabetic kidney disease.
Rui ZhangChunmei QinJunlin Zhangnull HonghongRenYiting WangYucheng WuLijun ZhaoJiali WangJie ZhangFang LiuPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2024)
Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process. Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE -/- DM) was generated from ApoE knockout (ApoE -/- ) mice using a high-fat and high-glucose diet combined with low-dose streptozocin intraperitoneal injection. We also established an in vitro model using HK2 cells. A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE -/- DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE -/- DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and downregulated the expression of PKCβ/P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high-glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing downregulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406). In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD-associated oxidative stress and apoptosis via downregulation of PKCβ/P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.
Keyphrases
- tyrosine kinase
- oxidative stress
- dna methylation
- gene expression
- induced apoptosis
- epidermal growth factor receptor
- genome wide
- signaling pathway
- cell cycle arrest
- endoplasmic reticulum stress
- poor prognosis
- high glucose
- randomized controlled trial
- binding protein
- low dose
- pi k akt
- high fat diet
- cognitive decline
- dna damage
- transcription factor
- cell death
- type diabetes
- copy number
- ischemia reperfusion injury
- endothelial cells
- physical activity
- mouse model
- reactive oxygen species
- radiation therapy
- skeletal muscle
- long non coding rna
- cell proliferation
- insulin resistance
- high resolution
- metabolic syndrome
- squamous cell carcinoma
- neoadjuvant chemotherapy
- dna binding
- wild type
- circulating tumor