Donor Dependent Variations in Systemic Oxidative Stress and Their Association with One-Year Graft Outcomes In Kidney Transplantation.

INTRODUCTION: Oxidative stress has been implicated in complications after kidney transplantation (KT), including delayed graft function and rejection. However, its role in long-term post-transplant outcomes remains unclear. METHODS: We investigated oxidative damage and antioxidant defense dynamics, and their impact on the graft outcomes, in 41 KT recipients categorized by type of donation over 12 months. Oxidative status was determined using OxyScore and AntioxyScore indexes, which comprise several circulating biomarkers of oxidative damage and antioxidant defense. Donor types included donation after brain death (DBD [61.0%]), donation after circulatory death (DCD [26.8%]) and living donation (LD [12.1%]). RESULTS: There was an overall increase in oxidative damage early after transplantation, which was significantly higher in DCD as compared to DBD and LD recipients. The multivariate adjustment confirmed the independent association of OxyScore and type of deceased donation with delayed graft function, donor kidney function and induction therapy with anti-thymocyte globulin. There were no differences in terms of antioxidant defense. Lower oxidative damage at day 7 predicted better graft function at one year post-transplant only in DBD recipients. CONCLUSION: DCD induced greater short-term oxidative damage after KT, whereas the early levels of oxidative damage were predictive of the graft function one year after KT among DBD recipients.

Impaired Mitophagy and Protein Acetylation Levels in Fibroblasts from Parkinson's Disease Patients.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S leucine-rich repeat kinase 2 (LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S LRRK2 mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S LRRK2 mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect.

Deficiency of NOD1 Improves the ß-Adrenergic Modulation of Ca2+ Handling in a Mouse Model of Heart Failure.

Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during ß-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the ß-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of ß1 and ß2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under ß-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the ß-adrenergic modulation of Ca2+ handling in failing hearts.