Genotoxic damage in end-stage renal disease

Gandhi, Gursatej; Mehta, Trupti R.; Contractor, P.; Tung, Gurleen Kaur

doi:10.1016/j.mrgentox.2018.08.005

Cited by 11 publications

(7 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For starters, renal and systemic inflammation are significant causes of ESRD in patients with kidney diseases [35]. Furthermore, multiple studies have revealed that TFs, DNA, and chromosome damage, as well as metabolites in urine and blood, are all linked to the development of ESRD and can be manifested to be potential diagnostic and prognostic biomarkers [36][37][38]. However, there are currently no daily clinical examinational biomarkers for ESRD.…”

Section: Discussionmentioning

confidence: 99%

The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease

Peng

Zhang

et al. 2023

Eur J Med Res

View full text Add to dashboard Cite

Background End-stage renal disease (ESRD) is the final stage of chronic kidney disease (CKD). In addition to the structurally intact chromosome genomic DNA, there is a double-stranded circular DNA called extrachromosomal circular DNA (eccDNA), which is thought to be involved in the epigenetic regulation of human disease. However, the features of eccDNA in ESRD patients are barely known. In this study, we identified eccDNA from ESRD patients and healthy people, as well as revealed the characteristics of eccDNA in patients with ESRD. Methods Using the high-throughput Circle-Sequencing technique, we examined the eccDNA in peripheral blood mononuclear cells (PBMCs) from healthy people (NC) (n = 12) and ESRD patients (n = 16). We analyzed the length distribution, genome elements, and motifs feature of eccDNA in ESRD patients. Then, after identifying the specific eccDNA in ESRD patients, we explored the potential functions of the target genes of the specific eccDNA. Finally, we investigated the probable hub eccDNA using algorithms. Results In total, 14,431 and 11,324 eccDNAs were found in the ESRD and NC groups, respectively, with sizes ranging from 0.01 kb to 60 kb at most. Additionally, the ESRD group had a greater distribution of eccDNA on chromosomes 4, 11, 13, and 20. In two groups, we also discovered several motifs of specific eccDNAs. Furthermore, we identified 13,715 specific eccDNAs in the ESRD group and 10,585 specific eccDNAs in the NC group, both of which were largely annotated as mRNA catalog. Pathway studies using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the specific eccDNA in ESRD was markedly enriched in cell junction and communication pathways. Furthermore, we identified potentially 20 hub eccDNA-targeting genes from all ESRD-specific eccDNA-targeting genes. Also, we found that 39 eccDNA-targeting genes were associated with ESRD, and some of these eccDNAs may be related to the pathogenesis of ESRD. Conclusions Our findings revealed the characteristics of eccDNA in ESRD patients and discovered potentially hub and ESRD-relevant eccDNA-targeting genes, suggesting a novel probable mechanism of ESRD.

show abstract

Section: Discussionmentioning

confidence: 99%

The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease

Peng

Zhang

et al. 2023

Eur J Med Res

View full text Add to dashboard Cite

show abstract

“…It has been reported in various studies that genotoxic damage increases in chronic renal failure, in both the predialysis and the dialysis phase [ 64 , 65 , 66 , 67 , 68 ]. In a study with 24 age- and sex-matched healthy subjects, 22 non-dialyzed patients with advanced renal failure, and 42 chronic peritoneal-dialysis patients, a profound increase in 8-OHdG levels in peripheral leukocyte DNA occurred during chronic renal failure, gradually increasing with disease progression [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the study by Gandhi et al [ 68 ] with 55 ESRD patients undergoing dialysis and 39 healthy controls, increases in DNA damage and micronucleus frequency were shown in patients using the single-cell gel electrophoresis assay and the micronucleus test, respectively. In this study, it was reported that time-on-medication and time-on-dialysis were correlated with genetic damage.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Biomonitoring of Oxidative-Stress-Related Genotoxic Damage in Patients with End-Stage Renal Disease

Yüzbaşıoğlu,

Hazar,

Aydın Dilsiz

et al. 2024

Toxics

View full text Add to dashboard Cite

Chronic kidney disease (CKD), a common progressive renal failure characterized by the permanent loss of functional nephrons can rapidly progress to end-stage renal disease, which is known to be an irreversible renal failure. In the therapy of ESRD, there are controversial suggestions about the use of regular dialysis, since it is claimed to increase oxidative stress, which may increase mortality in patients. In ESRD, oxidative-stress-related DNA damage is expected to occur, along with increased inflammation. Many factors, including heavy metals, have been suggested to exacerbate the damage in kidneys; therefore, it is important to reveal the relationship between these factors in ESRD patients. There are very few studies showing the role of oxidative-stress-related genotoxic events in the progression of ESRD patients. Within the scope of this study, genotoxic damage was evaluated using the comet assay and 8-OHdG measurement in patients with ESRD who were undergoing hemodialysis. The biochemical changes, the levels of heavy metals (aluminum, arsenic, cadmium, lead, and mercury) in the blood, and the oxidative biomarkers, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels were evaluated, and their relationship with genotoxic damages was revealed. Genotoxicity, oxidative stress, and heavy-metal levels, except mercury, increased significantly in all renal patients. DNA damage, 8OHdG, and MDA significantly increased, and GSH significantly decreased in patients undergoing dialysis, compared with those not having dialysis. The duration and the severity of disease was positively correlated with increased aluminum levels and moderate positively correlated with increased DNA damage and cadmium levels. In conclusion, this study revealed that the oxidative-stress-related DNA damage, and also the levels of Al and Cd, increased in ESRD patients. It is assumed that these changes may play an important role in the progression of renal damage. Approaches for reducing oxidative-stress-related DNA damage and heavy-metal load in ESRD patients are recommended.

show abstract

“…A major source of endogenous DNA damage in kidney tubular cells is the overproduction of reactive oxygen species (ROS), which can result from impaired mitochondrial oxidative metabolism, lowered antioxidant capacity, or impaired DNA repair mechanisms [ 16 , 17 ]. Regardless of the etiology, intracellular accumulation of ROS is associated with increased oxidative stress and oxidative DNA damage in the kidneys and is implicated in the development and progression of chronic kidney disease in humans [ 18 , 19 , 20 , 21 , 22 ]. The mitochondrial electron transport chain (ETC) is one of the major sources of endogenous ROS under normal aerobic conditions due to electron leakage at complexes I and III [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys

et al. 2023

View full text Add to dashboard Cite

Karyomegalic interstitial nephritis (KIN) is a genetic adult-onset chronic kidney disease (CKD) characterized by genomic instability and mitotic abnormalities in the tubular epithelial cells. KIN is caused by recessive mutations in the FAN1 DNA repair enzyme. However, the endogenous source of DNA damage in FAN1/KIN kidneys has not been identified. Here we show, using FAN1-deficient human renal tubular epithelial cells (hRTECs) and FAN1-null mice as a model of KIN, that FAN1 kidney pathophysiology is triggered by hypersensitivity to endogenous reactive oxygen species (ROS), which cause chronic oxidative and double-strand DNA damage in the kidney tubular epithelial cells, accompanied by an intrinsic failure to repair DNA damage. Furthermore, persistent oxidative stress in FAN1-deficient RTECs and FAN1 kidneys caused mitochondrial deficiencies in oxidative phosphorylation and fatty acid oxidation. The administration of subclinical, low-dose cisplatin increased oxidative stress and aggravated mitochondrial dysfunction in FAN1-deficient kidneys, thereby exacerbating KIN pathophysiology. In contrast, treatment of FAN1 mice with a mitochondria-targeted ROS scavenger, JP4-039, attenuated oxidative stress and accumulation of DNA damage, mitigated tubular injury, and preserved kidney function in cisplatin-treated FAN1-null mice, demonstrating that endogenous oxygen stress is an important source of DNA damage in FAN1-deficient kidneys and a driver of KIN pathogenesis. Our findings indicate that therapeutic modulation of kidney oxidative stress may be a promising avenue to mitigate FAN1/KIN kidney pathophysiology and disease progression in patients.

show abstract

Genotoxic damage in end-stage renal disease

Cited by 11 publications

References 49 publications

The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease

The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease

Biomonitoring of Oxidative-Stress-Related Genotoxic Damage in Patients with End-Stage Renal Disease

Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys

Contact Info

Product

Resources

About