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Functional methylome analysis of human diabetic kidney disease
Jihwan Park, … , Matthew Palmer, Katalin Susztak
Jihwan Park, … , Matthew Palmer, Katalin Susztak
Published June 6, 2019
Citation Information: JCI Insight. 2019;4(11):e128886. https://doi.org/10.1172/jci.insight.128886.
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Research Article Genetics

Functional methylome analysis of human diabetic kidney disease

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Abstract

In patients with diabetes mellitus, poor metabolic control has a long-lasting impact on kidney disease development. Epigenetic changes, including cytosine methylation, have been proposed as potential mediators of the long-lasting effect of adverse metabolic events. Our understanding of the presence and contribution of methylation changes to disease development is limited because of the lack of comprehensive base-resolution methylome information of human kidney tissue samples and site-specific methylation editing. Base resolution, whole-genome bisulfite sequencing methylome maps of human diabetic kidney disease (DKD) tubule samples, and associated gene expression measured by RNA sequencing highlighted widespread methylation changes in DKD. Pathway analysis highlighted coordinated (methylation and gene expression) changes in immune signaling, including tumor necrosis factor alpha (TNF). Changes in TNF methylation correlated with kidney function decline. dCas9-Tet1–based lowering of the cytosine methylation level of the TNF differentially methylated region resulted in an increase in the TNF transcript level, indicating that methylation of this locus plays an important role in controlling TNF expression. Increasing the TNF level in diabetic mice increased disease severity, such as albuminuria. In summary, our results indicate widespread methylation differences in DKD kidneys and highlights epigenetic changes in the TNF locus and its contribution to the development of nephropathy in patients with diabetes mellitus.

Authors

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

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Figure 6

Higher TNF levels augment diabetic albuminuria and cell death.

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Higher TNF levels augment diabetic albuminuria and cell death.
(A) Tnf e...
(A) Tnf expression in kidneys of wild-type and Ins2Akita mice (GSE87899) (34). (B) Tnf expression in kidneys of db/m and db/db mice (GSE87359) (35). (C) The urinary albumin-to-creatinine ratio using the urine collected from control, STZ-treated, and STZ/TNF–cotreated mice at 4, 8, and 24 hours following TNF injection. (D) Representative images of TUNEL assay of mouse kidney samples from STZ-treated and STZ/TNF–cotreated mice. (E) Quantification of positive cells per field as in D. (F) Relative transcript levels of Bcl2 and Bax in kidney samples dissected at 8 and 24 hours following TNF injection from control, STZ-treated, and STZ/TNF–cotreated mice. All data are presented as means ± SEM of 3 experiments and analyzed by 1-way ANOVA with Tukey’s post hoc test. Scale bars: 20 μm.

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