Epigenetic Risk Profile of Diabetic Kidney Disease in High-Risk Populations
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Purpose of Review
Epigenetic variations have been shown to reveal vulnerability to diabetes and its complications. Although it has become clear that metabolic derangements, especially hyperglycemia, can impose a long-term metabolic memory that predisposes to diabetic complications, the underlying mechanisms remain to be understood. It has been suggested that epigenetics (e.g., histone modification, DNA methylation, and non-coding RNAs) help link metabolic disruption to aberrancies related to diabetic kidney disease (DKD). In this review, we discuss the key findings and advances made in the epigenetic risk profile of DKD and provide perspectives on the emerging topics that implicate epigenetics in DKD.
Epigenetic profiles can be profoundly altered in patients with diabetes, in circulating blood cells as well as in renal tissues. These changes provide useful insight into the mechanisms of diabetic kidney injury and progressive kidney dysfunction.
Increasing evidence supports the role of epigenetic regulation in DKD. More studies are needed to elucidate the mechanism and importance of epigenetic changes in the initiation and progression of DKD and to further explore their diagnostic and therapeutic potential in the clinical management of patients with diabetes who have a high risk for DKD.
KeywordsDiabetic nephropathy Diabetic kidney disease Epigenetic regulation
The authors would like to acknowledge the support from Ella Fitzgerald Foundation. We apologize to colleagues whose important primary studies we were unable to cite due to space constraints.
This work was supported by the National Natural Science Fund of China 81570609 and 81770667 (to X. L.), and US PHS NIH research grants K99/R00HL122368 (to Z.C.) and R01 DK065073, R01 DK081705, R01DK58191, R01 HL106089 (to R.N.).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 2.Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108(17):1054–69.CrossRefGoogle Scholar
- 15.Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Lachin JM, Genuth S, Cleary PA, Davis MD, Nathan DM. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381–9.CrossRefGoogle Scholar
- 24.•• Chen Z, Miao F, Paterson AD, Lachin JM, Zhang L, Schones DE, et al. Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci USA. 2016;113(21):E3002–11. This study reports that the DNA-methylation differences during the DCCT persist at certain loci associated with glycemia for years during the EDIC Study and highlights an epigenetic explanation for metabolic memory.PubMedCrossRefGoogle Scholar
- 57.• Chu AY, Tin A, Schlosser P, Ko YA, Qiu C, Yao C, et al. Epigenome-wide association studies identify DNA methylation associated with kidney function. Nat Commun. 2017;8(1):1286. This well-powered EWAS identified differential DNA methylation associated with kidney function and CKD. It further demonstrated methylation at PTPN6 / PHB2 in kidney cortex was associated with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis.PubMedPubMedCentralCrossRefGoogle Scholar
- 71.Sayyed SG, Gaikwad AB, Lichtnekert J, Kulkarni O, Eulberg D, Klussmann S, et al. Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10. Nephrol Dial Transplant. 2010;25(6):1811–7.PubMedCrossRefPubMedCentralGoogle Scholar
- 81.• Kato M, Wang M, Chen Z, Bhatt K, Oh HJ, Lanting L, et al. An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun. 2016;7:12864. This study provides a thorough description of Lnc-MGC, a lncRNA megacluster regulated by endothplasmic reticulum stress and its relevance to human DKD.PubMedPubMedCentralCrossRefGoogle Scholar
- 82.• Long J, Badal SS, Ye Z, Wang Y, Ayanga BA, Galvan DL, et al. Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy. J Clin Invest. 2016;126(11):4205–18. This study provides extensive evidence for an important regulatory crosstalk between lncRNAs and mitochondria mitochondrial bioenergetics in podocytes in the diabetic milieu.PubMedPubMedCentralCrossRefGoogle Scholar