Mitochondrial dysregulation and oxidative stress in patients with chronic kidney disease

Granata, Simona; Zaza, Gianluigi; Simone, Simona; Villani, Gaetano; Latorre, Daniela; Pontrelli, Paola; Carella, Massimo; Schena, Francesco Paolo; Grandaliano, Giuseppe; Pertosa, Giovanni

doi:10.1186/1471-2164-10-388

Cited by 211 publications

(180 citation statements)

References 45 publications

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“…21 Cross-sectional studies of patients with CKD have shown that lower mitochondrial function, indicated by metabolites from urine and gene expression from peripheral blood, correlated with more severe CKD. 22,23 In this study, the association between mtDNA copy number and incident CKD was slightly attenuated after controlling for WBC count, a marker of systematic inflammation, but remained independent of WBC count and hsCRP. These results suggest mtDNA copy number may represent the effect of cumulative exposure to oxidative stress that is not captured in the one-time measures of WBC count and hsCRP.…”

Section: Main Findingsmentioning

confidence: 85%

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Tin

Grams²,

Ashar

et al. 2016

JASN

116

108

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Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of CKD. Mitochondrial DNA (mtDNA) copy number is a surrogate measure of mitochondrial function, and higher mtDNA copy number in peripheral blood has been associated with lower risk of two important risk factors for CKD progression, diabetes and microalbuminuria. We evaluated whether mtDNA copy number in peripheral blood associates with incident CKD in a population-based cohort of middle-aged adults. We estimated mtDNA copy number using 25 high-quality mitochondrial single nucleotide polymorphisms from the Affymetrix 6.0 array. Among 9058 participants, those with higher mtDNA copy number had a lower rate of prevalent diabetes and lower C-reactive protein levels and white blood cell counts. Baseline eGFR did not differ significantly by mtDNA copy number. Over a median follow-up of 19.6 years, 1490 participants developed CKD. Higher mtDNA copy number associated with lower risk of incident CKD (highest versus lowest quartile: hazard ratio 0.65; 95% confidence interval, 0.56 to 0.75; P,0.001) after adjusting for age, sex, and race. After adjusting for additional risk factors of CKD, including prevalent diabetes, hypertension, C-reactive protein level, and white blood cell count, this association remained significant (highest versus lowest quartile: hazard ratio 0.75; 95% confidence interval, 0.64 to 0.87; P,0.001). In conclusion, higher mtDNA copy number associated with lower incidence of CKD independent of traditional risk factors and inflammation biomarker levels in this cohort. Further research on modifiable factors influencing mtDNA copy number may lead to improvement in the prevention and treatment of CKD.

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Section: Main Findingsmentioning

confidence: 85%

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Tin

Grams²,

Ashar

et al. 2016

JASN

116

108

View full text Add to dashboard Cite

show abstract

“…27 The third most interconnected pathway, the NRF2 oxidative stress pathway, links to the relevance of oxidative stress in CKD, particularly in DN. [28][29][30] In general, low concentrations of prooxidants have potentially protective effects, because they act as secondary messengers of cell survival. 31 Excessive oxidative stress, however, is highly prevalent in patients with CKD and believed to contribute to more traditional cardiovascular risk factors in this patient cohort.…”

Section: The Ckd Pathway Network: Crosstalk Among Multiple Molecular mentioning

confidence: 99%

Integrative Biology Identifies Shared Transcriptional Networks in CKD

Martini

Nair

Keller

et al. 2014

Journal of the American Society of Nephrology

119

115

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A previous meta-analysis of genome-wide association data by the Cohorts for Heart and Aging Research in Genomic Epidemiology and CKDGen consortia identified 16 loci associated with eGFR. To define how each of these single-nucleotide polymorphisms (SNPs) could affect renal function, we integrated GFRassociated loci with regulatory pathways, producing a molecular map of CKD. In kidney biopsy specimens from 157 European subjects representing nine different CKDs, renal transcript levels for 18 genes in proximity to the SNPs significantly correlated with GFR. These 18 genes were mapped into their biologic context by testing coregulated transcripts for enriched pathways. A network of 97 pathways linked by shared genes was constructed and characterized. Of these pathways, 56 pathways were reported previously to be associated with CKD; 41 pathways without prior association with CKD were ranked on the basis of the number of candidate genes connected to the respective pathways. All pathways aggregated into a network of two main clusters comprising inflammation-and metabolism-related pathways, with the NRF2-mediated oxidative stress response pathway serving as the hub between the two clusters. In all, 78 pathways and 95% of the connections among those pathways were verified in an independent North American biopsy cohort. Disease-specific analyses showed that most pathways are shared between sets of three diseases, with closest interconnection between lupus nephritis, IgA nephritis, and diabetic nephropathy. Taken together, the network integrates candidate genes from genome-wide association studies into their functional context, revealing interactions and defining established and novel biologic mechanisms of renal impairment in renal diseases.

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“…These functional alterations in the liver might be derived from the enhancement of oxidative stress. Many past studies demonstrated that patients with kidney disease are under a considerable level of oxidative stress [23,24]. Therefore, the systemic oxidative stress of these patients might interfere with specific hepatic functions, such as metabolism of sulfatides.…”

Section: Discussionmentioning

confidence: 99%

Acute kidney injury induced by protein-overload nephropathy down-regulates gene expression of hepatic cerebroside sulfotransferase in mice, resulting in reduction of liver and serum sulfatides

Zhang

Nakajima

Kamijo

et al. 2009

Biochemical and Biophysical Research Communications

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Sulfatides, possible antithrombotic factors belonging to sphingoglycolipids, are widely distributed in mammalian tissues and serum. We recently found that the level of serum sulfatides was significantly lower in hemodialysis patients than that in normal subjects, and that the serum level closely correlated to the incidence of cardiovascular disease. These findings suggest a relationship between the level of serum sulfatides and kidney function; however, the molecular mechanism underlying this relationship remains unclear. In the present study, the influence of kidney dysfunction on the metabolism of sulfatides was examined using an established murine model of acute kidney injury, protein-overload nephropathy in mice. Protein-overload treatment caused severe proximal tubular injuries within 4 days, and this treatment obviously decreased both serum and hepatic sulfatide levels. The sphingoid composition of serum sulfatides was very similar to that of hepatic ones at each time point, suggesting that the serum sulfatide level is dependent on the hepatic secretory ability of sulfatides. The treatment also decreased hepatic expression of cerebroside sulfotransferase (CST), a key enzyme in sulfatide metabolism, while it scarcely influenced the expression of the other sulfatide-metabolizing enzymes, including arylsulfatase A, ceramide galactosyltransferase, and galactosylceramidase. Pro-inflammatory responses were not detected in the liver of these mice; however, potential oxidative stress was increased. These results suggest that down-regulation of hepatic CST expression, probably affected by oxidative stress from kidney injury, causes reduction in liver and serum sulfatide levels. This novel mechanism, indicating the crosstalk between kidney injury and specific liver function, may prove useful for helping to understand the situation where human hemodialysis patients have low levels of serum sulfatides.

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Mitochondrial dysregulation and oxidative stress in patients with chronic kidney disease

Cited by 211 publications

References 45 publications

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Integrative Biology Identifies Shared Transcriptional Networks in CKD

Acute kidney injury induced by protein-overload nephropathy down-regulates gene expression of hepatic cerebroside sulfotransferase in mice, resulting in reduction of liver and serum sulfatides

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