Impaired NRF2 Inhibits Recovery from Ischemic Reperfusion Injury in the Aging Kidney.

Deteriorating kidney function is frequently observed in the elderly population, as well as vulnerability to acute kidney failure, such as ischemic/reperfusion injury (IRI), and inadequate recovery from IRI is one of the mechanisms of kidney dysfunction in the elderly. The potential mediators in the progression of kidney dysfunction in the aging kidney have not yet been clearly revealed. In this study, we investigated the role of nuclear factor erythroid 2-related factor 2 (NRF2), which is an essential regulator of cellular redox homeostasis, in restoring kidney function after IRI in the aging kidney. NRF2 expression decreased significantly in the kidneys of old mice, as well as histologic and functional renal recovery after IRI; 45-min renal pedicle clamping was retarded in old compared with young mice. Persistent renal injury during the recovery phase after IRI was aggravated in NRF2 knockout (KO) mice compared to wild-type mice. Oxidative stress occurred in NRF2 KO old mice during the IRI recovery phase along with decreased expression of mitochondrial OXPHOS-related proteins and a reduction in mitochondrial ATP content. In vitro, hypoxia/reoxygenation (H/R) injury was aggravated in senescent human proximal tubuloepithelial cells after NRF2 restriction using NRF2 siRNA, which also increased the level of oxidative stress and deteriorated mitochondrial dysfunction. Treating the mice with an NRF2 activator, CDDO-Me, alleviated the injury. These results suggest that NRF2 may be a therapeutic target for the aging kidney.

The association of Klotho gene polymorphism with the mortality of patients on maintenance dialysis.

Despite medical progress, high morbidity and mortality rates have persisted in patients with end-stage renal disease (ESRD). The role in atherosclerosis and cardiovascular disease of klotho, an aging process-related gene, has been highlighted. Genetic variation in klotho has been reported to be a risk factor for coronary artery disease and ischemic stroke. Regarding the significance of cardiovascular disease for the outcome of ESRD patients, we investigated whether genetic variation of klotho was associated with mortality in ESRD patients on hemodialysis. 478 patients on maintenance hemodialysis for more than 3 months at dialysis facilities affiliated with the Western Dialysis Physician Association were enrolled in September 2004. Patient survival was checked annually until September 2007. Genotypings of klotho in terms of G395A in the promoter region, C1818T in exon 4, and KL-VS was performed. 45 deaths (11.2%) occurred over 3 years. Mortality was higher in the GA+AA group than in the GG group (18.9% vs. 6.7%, respectively, p < 0.001). Kaplan-Meier analysis also revealed that the survival of the GA+AA group was worse than that of GG group (p = 0.002). Cox's proportional hazards regression analysis showed that age, A allele carrier status in G395A of klotho, hemoglobin, albumin and HDL cholesterol levels were the significant factors affecting survival of hemodialysis patients. The A allele of the G395A polymorphism of klotho may be associated with the risk of mortality in Korean hemodialysis patients. Age, hemoglobin, albumin and HDLC were also significant prognostic factors for survival in the present study.

Alpha-lipoic acid attenuates cisplatin-induced tubulointerstitial injuries through inhibition of mitochondrial bax translocation in rats.

BACKGROUND: Renal tubule cell apoptosis plays a pivotal role in cisplatin-induced nephrotoxicity. alpha-Lipoic acid (LA), a thiol antioxidant, is well known to be cytoprotective in various cell death models through its involvement in the death receptor apoptosis pathway. However, we hypothesized that LA would attenuate cisplatin-induced nephrotoxicity through inhibition of mitochondrial bax translocation in rats. METHODS AND MATERIALS: Sprague-Dawley rats were treated with cisplatin (7 mg/kg) with or without pretreatment with LA (100 mg/kg x 3 times). Renal function was evaluated based on blood urea nitrogen (BUN), serum creatinine, and fractional excretion of sodium. Tubular necrosis scores were assessed by light microscopy findings and apoptotic cell deaths by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Cytosolic bax, mitochondrial bax, cytochrome c, caspase-9 and caspase-3 were investigated using Western blot in each group. RESULTS: LA pretreatment significantly decreased both BUN and serum creatinine. Morphologically, both tubular necrosis and apoptosis of tubular cells were decreased significantly with LA pretreatment. LA attenuated the translocation of mitochondrial bax, reduced the release of cytochrome c, and decreased the expression of caspase-3 and caspase-9 serially in cisplatin nephrotoxicity. CONCLUSION: We demonstrated that LA attenuates cisplatin-induced renal tubular damages by inhibition of mitochondrial bax translocation in vivo.

Aldosterone Synthase Gene (CYP11B2) Polymorphism in Korean End-Stage Renal Disease Patients on Hemodialysis.

Aldosterone synthase gene (CYP11B2) -344C/T polymorphism has been reported to be associated with serum aldosterone level, urinary aldosterone excretion, blood pressure, and left ventricular size and mass. The aim of this study was to evaluate the relation between CYP11B2 polymorphism and end-stage renal disease (ESRD) in the Korean population and the association with CYP11B2 polymorphism and cardiovascular morbidity in ESRD patients on hemodialysis. Genotyping was performed in 134 control subjects and 271 ESRD patients for CYP11B2 polymorphism using polymerase chain reaction through subsequent cleavage with restriction enzyme. Also current blood pressure, demographic, anthropometric and biochemical variables were investigated. The genotype distribution did not differ between ESRD patients and controls and there were no significant differences in blood pressure, use of antihypertensive medication, left ventricular hypertrophy and cardiovascular disease among the three genotypes in ESRD patients on hemodialysis. Our findings do not support the hypothesis that CYP11B2 polymorphism may be associated with prevalence of ESRD and suggest that CYP11B2 polymorphism may not be a genetic marker for cardiovascular morbidity in Korean ESRD patients.

VEGF protects human cerebral hybrid neurons from in vitro ischemia.

Vascular endothelial growth factor (VEGF), the most potent angiogenic peptide, protects the neurons against experimental ischemia. However, its neuroprotective effect on human brain is unknown. The present study attempted to determine whether VEGF can protect human cerebral neurons in vitro. A1 human hybrid clonal neurons (human cerebral neuron + neuroblastoma cell) were exposed to hypoxia with glucose deprivation. Pretreatment with VEGF reduced the A1 cell death, and VEGFR-2/Flk-1 and VEGF increased with a neuroprotective effect. However, the human neuroblastoma or neuroglioma cells failed to show these findings. Our results suggest that VEGF can protect human cerebral neurons from cell death after an ischemic insult in vitro, which is correlated to both increased expression of VEGFR-2/Flk-1 and VEGF within the cells.