Blood DNA Methylation Predicts Diabetic Kidney Disease Progression in High Fat Diet-Fed Mice

Abstract

Diabetic kidney disease (DKD) progresses at different rates among patients with type 2 diabetes mellitus (T2D). Early identification of patients with a higher risk of DKD progression is essential to improve prognosis. Epigenetic modifications, particularly DNA methylation, have been independently implicated in T2D and chronic kidney disease. The current study aimed to determine changes in blood DNA methylation that reflects and predicts DKD progression. C57BL/6 mice were fed a high-fat diet (HFD) from weaning and subclassified into two groups, HFD-1 and HFD-2, according to urinary kidney injury marker KIM-1/creatinine ratios (low vs. high) and histological abnormalities (mild–moderate vs. advanced). DNA methylation profiles were determined by reduced representative bisulfide sequencing (RRBS). Our results confirmed early and established DKD at week 9 and week 32, respectively. At week 32, advanced kidney injury was associated with dysregulation of methylation and demethylation enzymes in the kidney. Blood RRBS revealed 579 and 203 differentially methylated sites (DMS) between HFD-1 and HFD-2 animals at week 32 and week 9, respectively, among which 11 were common. The DMS in blood and kidney at week 32 were both related to organ development, neurogenesis, cell junction, and Wnt signalling, while the DMS in blood at week 9 suggested a specific enrichment of kidney development processes. In conclusion, our data strongly support the implication of early blood DNA methylation modifications and DKD progression in T2D that could be used to improve the disease’s prognostication.

Nutrition and Developmental Origins of Kidney Disease

“…In hypertensive rats, it was demonstrated that maternal protein deficiency in addition to a high-salt diet in the offspring resulted in hypertension that was associated with hypermethylation of prostaglandin E receptor 1 (PTGER1) and hypomethylation of angiotensin II receptor type 2 (AGTR2), respectively, in the kidney [111,112]. Further, AGTR1 hypomethylation in the blood was shown to predict CKD progression in HFDfed mice in adulthood [113], supporting an important role for the DNA methylation of angiotensin receptors and the developmental origin of CKD. In a different study, FGR was found to downregulate the expression of 11β-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the kidney by altering the binding of transcriptional factor to promoter and DNA/histone methylation [114].…”

DNA methylation in peripheral blood is associated with renal aging and renal function decline: a national community study

“…Several studies have utilized whole blood DNA methylation data from humans and have shown that DNA methylation can predict age and is correlated with a lower estimated glomerular filtration rate (eGFR) and a higher risk of CKD [ 9 ]. Moreover, animal studies analyzing blood DNA have revealed dysregulation of methylation and demethylation enzymes in diabetic kidney disease, highlighting the potential of whole blood DNA methylation as a predictor of disease progression [ 10 ]. Additionally, our previous study demonstrated that ischemia–reperfusion injury-associated acute kidney injury (IRI-AKI) leads to hypermethylation in pericytes, contributing to the progression from AKI to CKD, indicating that methylation could be a therapeutic target [ 11 ].…”

Diet Modification before or during Pregnancy on Maternal and Foetal Outcomes in Rodent Models of Maternal Obesity

“…The programming effects of maternal obesity on the offspring are potentiated by postnatal diet-induced obesity [ 80 ]. Our previous rodent studies, and others, have shown that being born to an obese mother significantly potentiates the deleterious effects of an obesogenic diet, yielding reduced glucose tolerance, exaggerated insulin resistance, hepatic steatosis, and renal fibrosis [ 78 , 83 , 84 , 85 , 86 ]. Interestingly, offspring have also been shown to develop hyperphagia [ 77 ].…”