Abstract
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.
Highlights
Various stresses, including UV radiation, chemicals, reactive oxygen species (ROS), DNA replication errors and mechanical stress, cause DNA damage[1]
This study demonstrated the following results in patients with IgA nephropathy: (1) correlation between glomerular DNA double-strand breaks (DSBs) and DNA methylation, (2) association of podocyte DNA DSBs with podocytopathic features and (3) association of glomerular γH2AX or 5-methyl cytosine (5mC) levels with the slope of eGFR decline over one year
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]
Summary
Various stresses, including UV radiation, chemicals, reactive oxygen species (ROS), DNA replication errors and mechanical stress, cause DNA damage[1]. 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. The association of glomerular DNA DSBs and DNA methylation with disease progression has not been shown in IgA nephropathy, a previous study reported an association between 8-OHdG, an indicator of oxidative DNA damage, and interstitial fibrosis in IgA nephropathy[15]. The present study revealed an association of glomerular DNA DSBs with DNA methylation and eGFR decline over one year in IgA nephropathy patients
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