Functional methylome analysis of human diabetic kidney disease

Park, Jihwan; Guan, Yuting; Sheng, Xin; Gluck, Caroline; Seasock, Matthew J.; Hakimi, A. Ari; Qiu, Chengxiang; Pullman, James; Verma, Amit; Li, Hongzhe; Palmer, Matthew; Suszták, Katalin

doi:10.1172/jci.insight.128886

Cited by 62 publications

(55 citation statements)

References 44 publications

(51 reference statements)

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“…We previously reported that altered DNA methylation in podocytes is involved in the pathogenesis of chronic kidney disease 21,22 , and recently suggested that impaired DNA DSB repair is associated with altered DNA methylation in podocytes 9 . Emerging evidence indicates that epigenetic mechanisms may contribute to kidney disease progression, and recent studies have successfully indicated the importance of kidney DNA methylation on renal function in humans 23,24 , although the association of DNA DSBs with DNA methylation and renal function in human kidneys has not been investigated. The present study demonstrated that glomerular DNA DSBs were positively correlated with glomerular DNA methylation in each glomerulus, which is in agreement with our previous results in murine models.…”

Section: Discussionmentioning

confidence: 99%

Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy

Hayashi

Hishikawa

Hashiguchi

et al. 2020

Sci Rep

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Accumulation of DnA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DnA DSBs with altered DnA methylation in murine models of kidney disease. However, DSBs and DnA methylation in human kidneys was not adequately investigated. this study was a cross-sectional observational study to evaluate the glomerular DnA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance pcR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DnA methylation level in igA nephropathy. podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of pcR product of the nephrin gene, which indicate podocyte DnA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGfR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in igA nephropathy. Various stresses, including UV radiation, chemicals, reactive oxygen species (ROS), DNA replication errors and mechanical stress, cause DNA damage 1. Although various types of DNA damage have been reported, DNouble-strand breaks (DSBs) are biologically important because of the repair difficulty 2. Accumulation of DNA damage is linked to aging and age-related diseases, such as cancer. Recent studies reported that increased DNA damage and reduced DNA repair capacity also play roles in the pathogenesis of cardiovascular and metabolic diseases 3. Angiotensin II and aldosterone are key factors in kidney disease that cause DNA damage, such as DSBs, and DNA base modification, such as 8-OHdG 4,5. However, the association of DNA DSBs in human kidneys with clinical parameters and pathological findings has not been adequately elucidated. Previous in vitro studies suggested that DNA DSBs and their repair processes induced altered DNA methylation 6-8. We recently investigated the association of DNA DSBs with altered DNA methylation status in glomerular podocytes using murine models of diabetic nephropathy 9. Increased DNA DSBs in podocytes due to both decreased levels of the DNA repair factor KAT5 and increased DNA damage induced by high-glucose conditions increased DNA methylation in the nephrin promoter region. However, the association of DNA DSBs with DNA methylation status in human kidneys was not investigated. IgA nephropathy is the most common glomerulonephritis in many countries, especially countries in Asia...

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Section: Discussionmentioning

confidence: 99%

Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy

Hayashi

Hishikawa

Hashiguchi

et al. 2020

Sci Rep

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“…The case and control population employed in this study has >60% power to detect a true positive (defined as detected CpGs with a meaningful difference in mean blood derived DNA methylation ±0.2 with a false discovery rate P ≤ 0.05) association using pwrEWAS ( Graw et al, 2019 ). More comprehensive whole genome bisulfite sequencing has been reported for kidney biopsy samples from five individuals with DKD compared to one person with diabetes without kidney disease, and four people with neither diabetes nor kidney disease ( Park et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Differential DNA methylation has been associated with "metabolic memory" of glycemic control and with a higher risk of developing DKD (Swan et al, 2015;Keating et al, 2018;Aranyi and Susztak, 2019;Gluck et al, 2019;Gu, 2019;Jia et al, 2019;Park et al, 2019). As DKD is not clinically detectable until significant organ damage has developed (albuminuria and/or reduced eGFR), more effective diagnostic tools and treatments, guided by a better understanding of pathophysiology, are urgently required.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

Smyth

Patterson

Swan

et al. 2020

Front. Cell Dev. Biol.

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A subset of individuals with type 1 diabetes will develop diabetic kidney disease (DKD). DKD is heritable and large-scale genome-wide association studies have begun to identify genetic factors that influence DKD. Complementary to genetic factors, we know that a person's epigenetic profile is also altered with DKD. This study reports analysis of DNA methylation, a major epigenetic feature, evaluating methylome-wide loci for association with DKD. Unique features (n = 485,577; 482,421 CpG probes) were evaluated in blood-derived DNA from carefully phenotyped White European individuals diagnosed with type 1 diabetes with (cases) or without (controls) DKD (n = 677 samples). Explicitly, 150 cases were compared to 100 controls using the 450K array, with subsequent analysis using data previously generated for a further 96 cases and 96 controls on the 27K array, and de novo methylation data generated for replication in 139 cases and 96 controls. Following stringent quality control, raw data were quantile normalized and beta values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls; resultant P-values for array-based data were adjusted for multiple testing. Genes with significantly increased (hypermethylated) and/or decreased (hypomethylated) levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways. Twenty-two loci demonstrated statistically significant fold changes associated with DKD and additional support for these associated loci was sought using independent samples derived from patients recruited with similar inclusion criteria. Markers associated with CCNL1 and ZNF187 genes are supported as differentially regulated loci (P < 10 −8), with evidence also presented for AFF3, which has been identified from a meta-analysis and subsequent replication of genomewide association studies. Further supporting evidence for differential gene expression in CCNL1 and ZNF187 is presented from kidney biopsy and blood-derived RNA in people with and without kidney disease from NephroSeq. Evidence confirming that methylation sites influence the development of DKD may aid risk prediction tools and stimulate research to identify epigenomic therapies which might be clinically useful for this disease.

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“…Recently, the importance of kidney site-specific DNA methylation on renal function has been demonstrated in humans 22,23 . The present study has suggested that urine DNMTs/AQP1 was correlated with the rate of eGFR decline over one year, indicating that not only altered DNA methylation itself but also altered expression of DNA methylation modulators may be associated with disease progression.…”

Section: Discussionmentioning

confidence: 99%

DNA damage and expression of DNA methylation modulators in urine-derived cells of patients with hypertension and diabetes

Hishikawa

Hayashi

Yoshimoto

et al. 2020

Sci Rep

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Diabetes and hypertension have become the primary causes of chronic kidney disease worldwide. However, there are no established markers for early diagnosis or predicting renal prognosis. Here, we investigated the expression profiles of DNA repair and DNA methylation factors in human urinederived cells as a possible diagnostic or renal prognosis-predicting marker. A total of 75 subjects, aged 63.3 ± 1.9 years old, were included in this study. DNA and RNA were extracted from 50 mL of urine samples. We evaluated DnA double-strand breaks (DSBs) by the quantitative long distance-PCR method and performed real-time RT-PCR analysis to analyze the expression of renal cell-specific markers, DNA DSB repair factor KAT5, DNA methyltransferases DNMTs, and demethylation enzymes tets. in patients with hypertension and diabetes, DnA DSBs of the nephrin gene increased with decreased urine KAT5/nephrin expression, consistent with our previous study (Cell Rep 2019). In patients with hypertension, DNA DSBs of the AQP1 gene were increased with elevated urine DNMTs/ AQP1 and TETs/AQP1 expression. Moreover, urine DNMTs/AQP1 expression was significantly correlated with the annual eGFR decline rate after adjustment for age, baseline eGFR, the presence of diabetes and the amount of albuminuria, suggesting a possible role as a renal prognosis predictor. The prevalence of chronic kidney disease (CKD) has increased globally and become recognized as a worldwide health problem 1. Specifically, the number of CKD caused by diabetes or hypertension is constantly growing along with rapid aging of the world population. The DNA damage repair system is indispensable for maintaining genome integrity, and accumulation of DNA damage is linked to aging and age-related diseases. Recently, we have reported a possible association of KAT5 (lysine acetyltransferase 5, Tip60)-mediated DNA damage repair and DNA methylation changes in kidney glomerular podocytes 2. KAT5, a repair factor of DNA double-strand breaks (DSBs), is crucial for podocyte maintenance, and deletion of podocyte KAT5 caused an increase in DNA DSBs together with increased DNA methylation and expression of DNA methyltransferase 1 (DNMT1) and DNMT3B. Reduced KAT5 expression was observed in the glomeruli of diabetic nephropathy in mouse models and humans. However, the association of KAT5 expression with DNA DSB levels and kidney disease progression has not been clarified. A kidney biopsy is an invasive procedure that is not often performed in patients with an early stage of hypertension or diabetes. In addition, many histological findings of hypertensive nephrosclerosis and diabetic kidney disease are common and coexist; therefore, it is hard to determine which pathophysiology plays a dominant role in patients with both hypertension and diabetes. Urine examinations are noninvasive procedures, and because they identify changes in gene expression in urine-derived cells 3-6 , they may be particularly useful for the noninvasive assessment of kidney condition and prediction of renal outcomes in early ...

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Functional methylome analysis of human diabetic kidney disease

Cited by 62 publications

References 44 publications

Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy

Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy

DNA Methylation Associated With Diabetic Kidney Disease in Blood-Derived DNA

DNA damage and expression of DNA methylation modulators in urine-derived cells of patients with hypertension and diabetes

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