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Title: The role of dietary antioxidants against oxidant-induced acute kidney injury
Author: Elisha-Lambert, Benjamin
ISNI:       0000 0004 7427 0855
Awarding Body: University of Brighton
Current Institution: University of Brighton
Date of Award: 2018
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Acute kidney injury (AKI) is defined by a sudden loss of kidney function, within hours to days. The initiation and propagation of AKI corresponds to oxidative stress (OS) in the proximal convoluted tubule. AKI has increasing morbidity and mortality rates over the past decade, predominantly in patients admitted to intensive care. Treatments for AKI remain inadequate and reside in supportive care, increasing the requirement of renal replacement therapies (RRT). Dietary antioxidants, hydroxycinnamates (HXCs) small phenylpropanoid plant metabolites and resveratrol (RESV) a stilbene, have well established antioxidant properties and may provide prophylaxis against AKI. The effects of HXCs: para-coumaric acid (p-CA), meta-coumaric acid (m-CA), orthocoumaric acid (o-CA), caffeic acid (CFA), ferulic acid (FRA), sinapic acid (SAA) and chlorogenic acid (CGA) and stilbenoid, resveratrol were investigated in vitro in proximal convoluted tubular cells (NRK-52E cells). The effects of potent oxidants: Paraquat (PQ), hydrogen peroxide (H2O2), peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1) in NRK-52E cells. Cell viability (MTT), cell membrane integrity (LDH), superoxide generation (NBT), antioxidant capacity (ABTS•+) and the initiation of apoptosis or necrosis in vitro for the protection against OS in NRK-52E cells model of AKI. Attenuation of AKI by antioxidants (m-CA, FRAand RESV) was studied in vivo using a rat model of PQ-mediated AKI using biomarkers for kidney function (serum creatinine) and injury (β-NAG and KIM-1). HXCs and RESV demonstrated concentration-dependant antioxidant/pro-oxidant activity in NRK-52E cells in OS states. OS inducers (PQ, H2O2, ONOOandSIN-1) reduced cell viability and membrane integrity against differing concentrations (10μ10mM) and time-dependent (0-24 hours) manner. HXCs and RESV attenuated internally generated ROS (e.g. by PQ). Pre-treatment of HXCs and RESV demonstrated improved protection before exposure to OS-inducers. Protection from PQ-induced OS by treatment of HXCs and RESV was (in descending order): m-CA ≥ FRA > p-CA > RESV > CGA, CFA, o-CA > SAA. Protection has been attributed to scavenging of OS inducers (to generated ROS or binding to PQ) or boosting of the endogenous antioxidant defence before oxidant exposure. PQ-treatment had a concentration dependent reduction in the antioxidant capacity of the NRK-52E cells. Pre-treatment of HXC and RESV protected against this loss. Pre-treatment of m-CA, FRA and RESV increased apoptosis in NRK-52E cells during PQ exposure. The pre-treatment of HXCs and RESV against externally active oxidants (H2O2, SIN-1 and ONOO-) provided limited or no protection to NRK-52E cells. PQ-induced injury and loss to kidney function in vivo. Treatment of m-CA, FRA and RESV protected against loss to kidney function. However, kidney injury in m-CA and FRA interventions were present, although RESV treatment reduced kidney injury. The demonstrated effects of HXCs and RESV against oxidant-AKI implies additional roles in antioxidant defence, redox and cell survival signalling in the pathophysiology of the proximal convoluted tubules during AKI. In Summary, dietary antioxidants demonstrated protection to proximal tubular cells and the function of the kidney against oxidant-induced AKI. Principally, they attenuated in vitro and in vivo PQ-induced AKI. In lieu of antioxidant action, results suggest, HXCs and RESV have alternative esoteric effects in proximal tubule cells. The thesis may provide insights and understanding of the cellular mechanisms and pathophysiology of AKI and role of dietary antioxidants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available