Protective effect of dietary flaxseed oil on arsenic-induced nephrotoxicity and oxidative damage in rat kidney

Arsenic, a naturally occurring metalloid, is capable of causing acute renal failure as well as chronic renal insufficiency. Arsenic is known to exert its toxicity through oxidative stress by generating reactive oxygen species (ROS). Flaxseed, richest plant based dietary source of n 3 polyunsaturated fatty acids (PUFAs) and lignans have shown numerous health benefits. Present study investigates the protective effect of flaxseed oil (FXO) on sodium arsenate (NaAs) induced renal damage. Rats prefed with experimental diets (Normal or FXO diet) for 14 days, were administered NaAs (20 mg per kg body weight i.p.) once daily for 4 days while still on the experimental diets. NaAs nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. Administration of NaAs led to a significant decline in the specific activities of brush border membrane (BBM) enzymes both in kidney tissue homogenates and in the isolated membrane vesicles. Lipid peroxidation and total sulfhydryl groups were altered upon NaAs treatment, indicating the generation of oxidative stress. NaAs also decreased the activities of metabolic enzymes and antioxidant defence system. Histopathological studies supported the biochemical findings showing extensive damage to the kidney by NaAs. In contrast, dietary supplementation of FXO prior to and along with NaAs treatment significantly attenuated the NaAs induced changes. (Authors abstract)
Human exposure to metals/metalloids such as uranium, lead, arsenic (As) and cadmium in both occupational and environmental settings is a common occurrence. The major inorganic forms of arsenic include trivalent arsenite and pentavalent arsenate (AsV). Arsenic typically arsenate enters the body mainly via consumption of contaminated drinking water. Increasing evidence indicate that multifactorial mechanisms might be involved in metal induced toxicity and that one of the well known mechanism involves metal induced reactive oxygen species (ROS) generation. Arsenic is one of the most extensively studied metals that induce ROS generation and results in oxidative stress.  A number of animal studies involving dietary supplementation of flaxseed and FXO have reported inhibition of arrhythmogenesis during ischemia reperfusion, inhibition of atherogenesis and protection against vascular dysfunction during hypercholesterolemic conditions.  The efficacy of FXO to protect against arsenic induced nephrotoxicity has not yet been evaluated.  The present work was undertaken to study detailed biochemical events/cellular response/mechanisms of sodium arsenate (NaAs) nephropathy and its possible mitigation by FXO.  It washypothesized that FXO would prevent NaAs-induced adverse effects on kidney due to its intrinsic biochemical and antioxidant properties that would result in improved metabolism and antioxidant defense mechanism in the kidney.
Multiple injections of NaAs were found to cause marked renal  dysfunction as evident by increased serum creatinine (Scr) and BUN, diagnostic indicators of nephrotoxicity, accompanied bymassive polyuria, proteinuria, glucosuria, phosphaturia and decreased  creatinine clearance. These changes were associated with increased serum cholesterol and phospholipids but decreased serum Pi and glucose. Feeding of FXO enriched diet prior to and along with NaAs administration prevented NaAs induced alterations in various serum and urine parameters. FXO consumption significantly lowered NaAs elicited increased levels of Scr and BUN. Serum glucose and phosphate were also improved by dietary FXO supplementation.
FXO administration to NaAs treated rats resulted in an overall improvement of carbohydrate metabolism as evident by higher activities of LDH, MDH and gluconeogenic enzymes in NaAs FXO compared to NaAs alone or control groups. This could be attributed  to the fact that FXO might have lowered the number of damaged mitochondria or affected macromolecules or increased the number of normally active organelles or macromolecules.  ROS are important mediators of arsenic nephropathy. Metabolism of arsenic in the cells leads to the generation of ROS which are responsible for various toxic effects including oxidative damage to cellular macromolecules like DNA, proteins and lipids by disturbance of antioxidant defence system.
When FXO was administrated to NaAs treated rats the decline in SH content was prevented. The authors indicated this may be attributed to the possibility of arsenic getting chelated to the hydroxyl groups of lignans, which are the bioactive constituents of FXO. (note that this is inaccurate as FXO does not contain lignans) They also indicate that it appears that FXO enriched in n3 fatty acids and lignans enhanced resistance to free radical attack generated by NaAs administration.  Omega 3 fatty acids may contribute to effects but lignans would not. The authors conclude the present investigation indicate FXO, a major source of omega 3 fatty acids and phytoestrogenic lignans (an error) appears to improve membrane organization/integrity and functions. FXO might have accelerated the repair and/or regeneration of injured organelles  by strengthening endogenous antioxidant defense, FXO counteracted free radical mediated arsenic toxicity. (Editors comments)