Downregulation of Nuclear-Encoded Genes of Oxidative Metabolism in Dialyzed Chronic Kidney Disease Patients

Abstract

BackgroundMitochondria, essential eukaryotic cells organelles defined as the “powerhouse of the cell” because of their ability to produce the vast majority of energy necessary for cellular metabolism, may have a primary role in the oxidative stress-related intracellular machinery associated to chronic kidney disease (CKD).MethodsTo better assess this research assumption, we decided to study the key factors regulating mitochondrial oxidative metabolism in CKD patients in peritoneal dialysis (PD, n = 15) using several bio-molecular methodologies.ResultsRT-PCR experiments demonstrate that the expression level of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor-1 (NRF-1), two genes primarily involved in mitochondrial biogenesis and functions, were significantly hypo-expressed in peripheral blood mononuclear cells of PD patients compared to healthy subjects (HS, n = 15). Additionally, mRNA levels of several PGC1-α downstream target genes (TFAM, COX6C,COX7C, UQCRH and MCAD) were profoundly down-regulated in PD cells. TFAM protein analysis confirmed gene-expression results. High plasmatic concentration of Malondialdehyde found in PD patients, confirmed the contribution of the oxidative stress to these biological effects. Finally, Nuclear factor erythroid-derived 2-like 2 (NRF2 or NFE2L2), a transcription factor for numerous antioxidant/detoxifying enzymes and one of its target genes, superoxide dismutase-2 mitochondrial (SOD2) were up-regulated in PD compared to HS.ConclusionsOur results revealed, for the first time, that CKD-PD patients’ PBMC, through a complex intracellular biochemical machinery, are able to modulate their mitochondrial functions probably in the attempt to reduce oxidative metabolic damage and to turn on a valuable defense cellular strategy against oxidative stress.

Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2

“…Consequently inflammation-induced impairment of Nrf2 activation contributes to its depressed expression, as seen in the present study. It is of interest that, in a recent study, Zaza et al [39] found a significant increase in Nrf2 and SOD2 expressions in the PBMC of CKD patients maintained on peritoneal dialysis, contrasting the results found in hemodialysis patients. This may reflect the higher burden of inflammation in hemodialysis patients caused by intermittent blood exposure to the extracorporeal circuit and the dramatic rise and fall in body fluid volume during the inter-and intra-dialytic intervals.…”

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

“…[23][24][25] A large number of studies have shown that mitochondrial dysfunction plays an important role in the progression of renal disease including renal tubular injury, chronic kidney disease, and acute renal failure, which can lead to renal disease aggravation and progression. [26][27][28] More and more evidences suggested that the damage of mitochondrial morphological and function plays an important role in the development of DN. 29,30 Malik et al 31 found that mitochondrial DNA copy number of peripheral blood in patients with DN is significantly higher than the DM group without nephropathy, which prompted that mitochondrion plays a key role in DN, namely, mitochondrial fission is increasing under HG.…”

Renal Fibrosis and Mitochondrial Biogenesis

“…16,[19][20][21][22] Recently increasing evidences showed mitochondrial dysfunction in a broad spectrum of pathogenesis of renal diseases. Moreover renal diseases patients exhibited an impaired mitochondrial respiratory system.…”

“…Tubular epithelial cell damage causes from apoptosis/necrosis and epithelial-mesenchymal transition, additionally, endothelial dysfunction causes from apoptosis/necrosis and endothelial-mesenchymal transition. 18,19,[21][22][23][24][25][26] Studies have shown significantly increased ROS production, up-regulation of TGF-β expressions, high glucose levels, proteinuria, uremic toxins, ischemia/hypoxia, and activation of RAAS in peripheral blood mononuclear cells of patients, thereby demonstrating the close association between mitochondrial dysfunction and renal diseases progression. 21,25,27,28 Recently, a number of studies have revealed that regulation of co-activators can physiologically signal to specific transcription factor targets.…”

“…22,24,32,33 Subsequently, it was also found to be involved in the regulation of genes that play a role in a wide range of other biological functions, including signal transduction, organelle biogenesis, protein synthesis, cell growth, and the progression of the cell cycle. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Among the specific effects of relevance, mitochondrial transcription factor A, which promotes the transcription and replication of mitochondrial DNA, is up-regulated by NRF-1. Moreover, the distribution of NRF-1 in mammalian cells is pervasive, with the transcription factor also playing key parts in regulating tissue differentiation and development, gene expression, and anti-oxidative stress and inflammatory responses in a range of organisms.…”