Altered DNA methylation of TRIM13 in diabetic nephropathy suppresses mesangial collagen synthesis by promoting ubiquitination of CHOP

Abstract

Background: Mesangial collagen synthesis in renal glomeruli contributes to the pathogenesis of diabetic nephropathy (DN) which is one of the most serious complications of diabetes mellitus. However, the underlying mechanism of mesangial collagen synthesis is largely unknown. Methods: The differential expression of CHOP and TRIM13 which is a well-defined E3 ubiquitin ligase was compared in renal biopsy samples from DN/normal renal tissues, in isolated glomeruli of diabetic/control mice, as well as in high glucose (HG) or TGF-b1-stimulated renal mesangial cells. Then the relationship between TRIM13 and CHOP was explored using the ubiquitination assay. Findings: We found that the expression of TRIM13 was downregulated in renal biopsies, isolated glomeruli of diabetic mice, and HG/TGF-b1-stimulated renal mesangial cells, while the expression of CHOP was upregulated. An increased level of TRIM13 promoter methylation contributed to the deregulation of TRIM13 in renal glomeruli of DN. The ubiquitination assay confirmed that TRIM13 promoted ubiquitination and degradation of CHOP. Meanwhile, overexpressing TRIM13 attenuated DN-induced collagen synthesis and restored renal function in vitro and in vivo via downregulating CHOP. Interpretation: Our findings demonstrated that overexpressed TRIM13 suppresses mesangial collagen synthesis in DN by promoting ubiquitination of CHOP, suggesting TRIM13 as a potential therapeutic target in treating DN.

Urinary sediment microRNAs can be used as potential noninvasive biomarkers for diagnosis, reflecting the severity and prognosis of diabetic nephropathy

“…Approximately 40% of diabetic patients are prone to the development of diabetic nephropathy (DN) [ 2 – 4 ]. DN is one of the most common microvascular complications of diabetes and is considered the most common cause of end-stage renal disease (ESRD) [ 5 , 6 ]. Many scholars have found that some patients with diabetes and kidney disease have different clinical manifestations and sensitivities to treatment than those with typical DN [ 7 , 8 ].…”

Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

“…Most recently, a study in vitro and vivo suggested the tripartite motif-containing (TRIM13, a well-defined E3 ubiquitin ligase) promoted ubiquitination and degradation of C/EBP homologous protein (CHOP, associated with renal injury), which attenuated DN-induced collagen synthesis and restored renal function. 82 This finding provides new insights into the application of histone ubiquitin in the treatment of diabetic nephropathy. Based on existing literature and studies, additional research is required to expose the hidden targets of histone ubiquitination to prevent DN.…”

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice

“…In particular, ubiquitination and degradation of lysine-specific demethylase 3A and the downstream modulation of the TGF-β1/Smad2/Smad3 signaling induced by the plant extract magnoflorine attenuates DN and suppresses inflammatory responses and fibrosis in mesangial cells both in vitro and in vivo [ 27 ]. Mesangial collagen synthesis in DN is also modulated by the E3 ubiquitin ligase, TRIM13, by promoting ubiquitination and degradation of C/EBP homologous protein [ 28 ]. No data are available regarding the specific role of lysine 63 ubiquitination in mesangial cells under hyperglycemic conditions and further investigation is needed.…”