The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the primary microvascular complication of diabetes mellitus and may result in end-stage renal disease. The overproduction of various inflammatory factors is involved in the pathogenesis of DN. Protein tyrosine phosphatase 1B (PTP1B) modulates the expression of a series of cytokines and nuclear factor kappa B (NF-κB) activity. cAMP response element-binding protein (CREB) and lysine methyltransferase 5A (KMT5A) have been reported to participate in the maintenance of a healthy endothelium. In the present study, we hypothesise that CREB associates with KMT5A to modulate PTP1B expression, thus contributing to high glucose-mediated glomerular endothelial inflammation. Our analyses revealed that plasma inflammatory factor levels, glomerular endothelial p65 phosphorylation and PTP1B expression were increased in DN patients and rats. In vitro, high glucose increased endothelial inflammatory factor levels and p65 phosphorylation by augmenting PTP1B expression in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose decreased CREB and KMT5A expression. CREB overexpression and KMT5A overexpression both inhibited high glucose-induced PTP1B expression, p65 phosphorylation and endothelial inflammatory factor levels. si-CREB- and sh-KMT5A-induced p65 phosphorylation and endothelial inflammatory factor levels were reversed by si-PTP1B. Furthermore, CREB was associated with KMT5A. Mechanistic research indicated that CREB and histone H4 lysine 20 methylation (H4K20me1, a downstream target of KMT5A) occupy the PTP1B promoter region. sh-KMT5A augmented PTP1B promoter activity and activated the positive effect of si-CREB on PTP1B promoter activity. Our in vivo study demonstrated that CREB and KMT5A were downregulated in glomerular endothelial cells of DN patients and rats. In conclusion, CREB associates with KMT5A to promote PTP1B expression in vascular endothelial cells, thus contributing to hyperglycemia-induced inflammatory factor levels in DN patients and rats.

PTP1B inhibition ameliorates inflammatory injury and dysfunction in ox‑LDL‑induced HUVECs by activating the AMPK/SIRT1 signaling pathway via negative regulation of KLF2

“…Furthermore, the oxidative stress levels of the cells were also decreased following PTP1B knockdown. These findings were in consistency with previous reports, which showed that the upregulation of the combination of the cAMP response element-binding protein and lysine methyltransferase 5A inhibited the hyperglycemia-induced inflammatory factor levels by regulating PTP1B expression in vascular endothelial cells ( 40 ). These results suggested that PTP1B knockdown may protect HUVECs against inflammatory injury and dysfunction induced by ox-LDL.…”

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

“…PTP1B is localized on the cytoplasmic face of the endoplasmic reticulum by means of a hydrophobic C-terminal sequence that imposes a topological constraint on the ability of PTP1B to access its substrates. PTP1B is widely reported as a key regulator of metabolic signals, including insulin signaling and leptin signaling, that negatively regulate the insulin pathway through JAK2-STAT3 and CREB/lysine methyltransferase 5 A (KMT5A), which are dysfunctional in T2DM and obesity 11 , 168 , 169 (Fig. 8 ).…”

Protein Methylation in Diabetic Kidney Disease

“…Therefore, they can be marks of the active and repressive states of chromatin, thereby producing different developmental effects. Researchers have found that histone methylation plays an essential role in DKD progression ( 35 , 36 ).…”