Browsing by Subject "Reactive Oxygen Species"
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Item Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism(MDPI, 2021-10-23) Yan, Liang-Jun; Allen, Daniel C.Cadmium is a nonessential metal that has heavily polluted the environment due to human activities. It can be absorbed into the human body via the gastrointestinal tract, respiratory tract, and the skin, and can cause chronic damage to the kidneys. The main site where cadmium accumulates and causes damage within the nephrons is the proximal tubule. This accumulation can induce dysfunction of the mitochondrial electron transport chain, leading to electron leakage and production of reactive oxygen species (ROS). Cadmium may also impair the function of NADPH oxidase, resulting in another source of ROS. These ROS together can cause oxidative damage to DNA, proteins, and lipids, triggering epithelial cell death and a decline in kidney function. In this article, we also reviewed evidence that the antioxidant power of plant extracts, herbal medicines, and pharmacological agents could ameliorate cadmium-induced kidney injury. Finally, a model of cadmium-induced kidney injury, centering on the notion that oxidative damage is a unifying mechanism of cadmium renal toxicity, is also presented. Given that cadmium exposure is inevitable, further studies using animal models are warranted for a detailed understanding of the mechanism underlying cadmium induced ROS production, and for the identification of more therapeutic targets.Item Canonical Transient Receptor Potential 6 (TRPC6) Dysregulation in Mesangial Cells and Glomerular Hyperfiltration during the Early Stages of Diabetes(2010-12-01) Graham, Sarabeth M.; Rong MaGlomerular mesangial cells (MCs) regulate the glomerular filtration rate (GFR) by contracting and relaxing in response to agonists. The contractile function of MCs is controlled by intracellular Ca2+. Canonical Transient receptor potential 6 (TRPC6) contribute to Ca2+ signaling in a variety of cells. However, the physiological and pathological relevance of TRPC6 in MCs remains unknown. The present study was conducted to examine 1) if TRPC6 mediated an agonist-induced Ca2+ response in MCs and if this Ca2+ signaling mechanism was impaired in diabetes 2) the mechanism by which TRPC6 is dysregulated in diabetes. In the first study, angiotensin II (AngII)-stimulated membrane currents were significantly enhanced in TRPC6 overexpressing MCs, but significantly attenuated in cells with TRPC6 knockdown. AngII-induced calcium influx was suppressed in MCs with TRPC6 knockdown, as well as in MCs cultured in high glucose (HG). HG reduced both the mRNA and protein levels of TRPC6, but not other isoforms of TRPCs, in a time and dose dependent manner. Furthermore, in streptozotocin (STZ)-induced diabetic rat glomeruli, TRPC6 but not TRPC1 was downregulated. In the second study, we found that the diabetes-induced decrease in TRPC6 protein expression was specific for glomeruli and no change in TRPC6 expression was observed in the heart or aorta. In cultured MCs, hydrogen peroxide (H2O2) decreased TRPC6 protein expression in a dose and time dependent manner. Antioxidants prevented the inhibitory effect of HG on TRPC6 in MCs. Consistently, treatment of STZ-diabetic rats with tempol preserved TRPC6 in the glomeruli. Nox4 knockdown led to an increase in TRPC6 protein in MCs. Furthermore, PMA, but not its analog 4α-PDD, suppressed TRPC6 and this PMA effect was not altered by catalase. A PKC inhibitor, Gö6976, attenuated the downregulation of TRPC6 caused by both HG and H2O2. Taken together, these studies suggest that TRPC6 participates in Ca2+ signaling in MCs and hyperglycemia in diabetes downregulates TRPC6 protein expression through a Nox4-ROS-PKC pathway.Item INTERMITTENT HYPOXIA RELATED GENERATION OF REACTIVE OXYGEN SPECIES AND BAROREFLEX REGULATION OF BLOOD PRESSURE(2013-04-12) Lane, AphtonPurpose: The intermittent hypoxia related generation of reactive oxygen species (ROS) associated with obstructive sleep apnea (OSA) increases sympathetic activity. However, the specific role of ROS in establishing the hypertension associated with chronic OSA has not been identified. We hypothesize that the intermittent hypoxia (IH) induced production of ROS will reset the operating point of the Carotid Baroreflex to a higher mean arterial pressure (MAP). Methods: Human subjects (n = 11, 5 female) underwent neck pressure/suction (NP/NS) to assess carotid baroreflex (CBR) function before and after intermittent hypoxia training with or without the antioxidant, N-acetyl cysteine (NAC). During NP/NS, mean arterial pressure was recorded non-invasively using a finometer. Following baseline measurements for hemodynamic variables and CBR function, subjects were asked to ingest a drink containing either NAC or a placebo. One hour after ingestion, hemodynamic variables and CBR function were again measured, following which the subjects were intermittent hypoxia trained (IHT). Immediately after IHT, hemodynamic and CBR function measurements were repeated three times 30 minutes apart. A two-way analysis of variance (ANOVA) was used to analyze differences between treatment groups across time. Results: There were no changes in CBR function with NAC versus placebo across time (p=0.791). In addition, the assessment of the operating point of the MAP with NAC versus placebo across time was not different (p=0.62). Conclusions: These data indicate that the known scavenging effect of ROS on central Nitric Oxide enabling a greater central sympathetic outflow was counteracted by an unidentified local vasodilation resulting in an unchanged MAP. The lack of increase in resting MAP following IHT is in agreement with previous studies that report no change in MAP after IHT.Item Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases(Hindawi, 2019-11-11) Nandi, Ankita; Yan, Liang-Jun; Jana, Chandan Kumar; Das, NilanjanaReactive species produced in the cell during normal cellular metabolism can chemically react with cellular biomolecules such as nucleic acids, proteins, and lipids, thereby causing their oxidative modifications leading to alterations in their compositions and potential damage to their cellular activities. Fortunately, cells have evolved several antioxidant defense mechanisms (as metabolites, vitamins, and enzymes) to neutralize or mitigate the harmful effect of reactive species and/or their byproducts. Any perturbation in the balance in the level of antioxidants and the reactive species results in a physiological condition called "oxidative stress." A catalase is one of the crucial antioxidant enzymes that mitigates oxidative stress to a considerable extent by destroying cellular hydrogen peroxide to produce water and oxygen. Deficiency or malfunction of catalase is postulated to be related to the pathogenesis of many age-associated degenerative diseases like diabetes mellitus, hypertension, anemia, vitiligo, Alzheimer's disease, Parkinson's disease, bipolar disorder, cancer, and schizophrenia. Therefore, efforts are being undertaken in many laboratories to explore its use as a potential drug for the treatment of such diseases. This paper describes the direct and indirect involvement of deficiency and/or modification of catalase in the pathogenesis of some important diseases such as diabetes mellitus, Alzheimer's disease, Parkinson's disease, vitiligo, and acatalasemia. Details on the efforts exploring the potential treatment of these diseases using a catalase as a protein therapeutic agent have also been described.