DNA methylation enzymes in the kidneys of male and female BTBR ob/ob mice

Abstract

Diabetic kidney disease (DKD) is the leading cause of the end-stage renal disease. Recent studies have shown that epigenetic modifications contribute to alterations in gene expression and the development of DKD. This study aimed to show an expression profile of key DNA (de)methylation enzymes (DNMT, TET proteins) and their differences between sexes under obesity and diabetic condition. Male and female black and tan brachyury (BTBR) ob/ob mice and their corresponding wild-type littermates (BTBR WT) were studied until 16 weeks of age. Metabolic parameters, kidney morphophysiology and the expression of fibrotic markers and epigenetic enzymes were studied in whole kidney tissue or specifically in the glomerulus. The results showed sexual dimorphism in the development of metabolic disease and in kidney morphophysiology. Female mice have a different profile of DNMTs expression in both WT and obese/diabetic condition. Furthermore, metabolic condition negatively modulated the glomerular expression of TET1 and TET3 only in females. To our knowledge, this is the first study that shows a kidney profile of the expression of key (de)methylation enzymes, DNMTs and TETs, in the BTBR ob/ob experimental model of DKD and its association with sex. The knowledge of this epigenetic profile may help future research to understand the pathophysiology of DKD in males and females.

Role of Sex Hormones in Prevalent Kidney Diseases

“…Recent studies in complex diseases reveal the close relationship between sex hormones and epigenetic modifications, i.e., changes in gene expression patterns that are not directly related to the alteration of the DNA sequence itself [186,187]. Studies on epigenetic alterations in a mouse model of DKD have shown a sexual dimorphism in the expression of key (de)methylation enzymes [188], suggesting a possible link to differences in sex hormone expression between males and females. In CD4+ T cells from SLE patients, estradiol treatment inhibited DNA methyltransferase 1, causing global DNA hypomethylation [189].…”

Epigenetic modifications in obesity‐associated diseases

“…Advanced diabetes patients commonly experience a range of complications, increasing the complexity of treatment. Compared with normal mice, obese/diabetic mice show different expression patterns of DNMTs and TET proteins in their kidney tissues, which may promote the progression of diabetic nephropathy by regulating DNAm levels 79 . Ten‐eleven translocation methylcytosine dioxygenase 2 (TET2) can demethylate the CGI of transforming growth factor β1 (TGFB1) to promote glomerulosclerosis and accelerating the progression of diabetic nephropathy 80 .…”