Osthol Ameliorates Kidney Damage and Metabolic Syndrome Induced by a High-Fat/High-Sugar Diet.

Excessive intake of fructose results in metabolic syndrome (MS) and kidney damage, partly mediated by its metabolism by fructokinase-C or ketohexokinase-C (KHK-C). Osthol has antioxidant properties, is capable of regulating adipogenesis, and inhibits KHK-C activity. Here, we examined the potential protective role of osthol in the development of kidney disease induced by a Western (high-fat/high-sugar) diet. Control rats fed with a high-fat/high-sugar diet were compared with two groups that also received two different doses of osthol (30 mg/kg/d or 40 mg/kg/d body weight BW). A fourth group served as a normal control and received regular chow. At the end of the follow-up, kidney function, metabolic markers, oxidative stress, and lipogenic enzymes were evaluated. The Western diet induced MS (hypertension, hyperglycemia, hypertriglyceridemia, obesity, hyperuricemia), a fall in the glomerular filtration rate, renal tubular damage, and increased oxidative stress in the kidney cortex, with increased expression of lipogenic enzymes and increased kidney KHK expression. Osthol treatment prevented the development of MS and ameliorated kidney damage by inhibiting KHK activity, preventing oxidative stress via nuclear factor erythroid 2-related factor (Nrf2) activation, and reducing renal lipotoxicity. These data suggest that the nutraceutical osthol might be an ancillary therapy to slow the progression of MS and kidney damage induced by a Western diet.

A Role for Both V1a and V2 Receptors in Renal Heat Stress Injury Amplified by Rehydration with Fructose.

Chronic vasopressin secretion induced by recurrent mild heat stress exposure is significantly enhanced by limited rehydration with a fructose-containing beverage both in rodents and in humans. Moreover, this effect has been associated with upregulation of the polyol-fructokinase pathway and increased renal oxidative stress. Previously, we have shown that pharmacological inhibition of both V1a and V2 vasopressin receptors with conivaptan improved such renal alterations. The aim of this study was to evaluate the independent contributions of V1a and V2 receptors to the renal damage caused by mild heat stress and limited rehydration with a fructose-containing beverage. Osmotic minipumps were used to deliver either relcovaptan (0.64 mg/day) or tolvaptan (0.25 mg/day) in male Wistar rats for two weeks. Corresponding dilution vehicles were used as controls. To induce dehydration, rats were exposed to mild heat stress (37 °C for 1 h, Monday to Friday). All groups received a 10% fructose solution as a rehydration fluid for 2 h after mild heat stress. For the remainder of the day and on weekends, rats received tap water. The independent blockade of either the V1a or the V2 receptor prevented renal damage, reduced oxidative stress, and decreased plasma cortisol and systemic inflammation. However, the beneficial effects were regulated by different mechanisms. Tolvaptan inhibited polyol-fructokinase pathway overactivation, while relcovaptan prevented upregulation of the renin-angiotensin system and SGK1 expression. These data suggest that both V1a and V2 receptors participate in renal damage caused by heat stress-induced dehydration when fructose-containing beverages are used as rehydration fluids.

Kidney Injury from Recurrent Heat Stress and Rhabdomyolysis: Protective Role of Allopurinol and Sodium Bicarbonate.

BACKGROUND: Heat stress and rhabdomyolysis are major risk factors for the occurrence of repeated acute kidney injury in workers exposed to heat and strenuous work. These episodes, in turn, may progress to chronic kidney disease. OBJECTIVE: The purpose of this study was to test the effect of allopurinol (AP) and sodium bicarbonate on the kidney injury induced by recurrent heat stress dehydration with concomitant repeated episodes of rhabdomyolysis. METHODS: The model consisted of heat stress exposure (1 h, 37°C) plus rhabdomyolysis (R) induced by repetitive IM injections of glycerol (7.5 mL/kg BW days) in the rat. In addition, to replicate the human situation, uricase was inhibited (oxonic acid [OA] 750 mg/K/d) to increase uric acid (UA) levels. Additional groups were treated either with AP 150 mg/L, n = 10, bicarbonate (BC; 160 mM, n = 10), or both (AP + BC, n = 10) in drinking water. We also included 2 control groups consisting of normal controls (N-Ref, n = 5) and uricase-inhibited rats (OA, n = 5) that were not exposed to heat or muscle injury. Groups were studied for 35 days. RESULTS: Uricase-inhibited rats exposed to heat and rhabdomyolysis developed pathway and increased intrarenal oxidative stress and inflammasome activation. Kidney injury could be largely prevented by AP, and also BC, although the treatments were not synergistic. CONCLUSION: Increased levels of UA may play an important role in the renal alterations induced by heat stress and continuous episodes of rhabdomyolysis. Therefore, treatments aimed to reduce hyperuricemia may help to decrease the renal burden in these conditions. Clinical trials are suggested to test whether this is also true in humans.

Fluid Intake Restriction Concomitant to Sweetened Beverages Hydration Induce Kidney Damage.

Currently, there is the paradox of low water intake but increased intake of sugar-sweetened beverages (SB) in several populations; those habits are associated with an increased prevalence of metabolic derangements and greater chronic disease mortality. Persistent heat dehydration and increased SB intake stimulate the continued release of vasopressin and overactivation of the polyol-fructokinase pathway, synergizing each other, an effect partially mediated by oxidative stress. The objective of the present study was to evaluate whether water restriction concurrent with SB hydration can cause renal damage by stimulating similar pathways as heat dehydration. Three groups of male Wistar rats (n = 6) were fluid restricted; from 10 am to 12 pm animals could rehydrate with tap water (W), or sweetened beverages, one prepared with 11% of a fructose-glucose combination (SB), or with the noncaloric edulcorant stevia (ST). A normal control group of healthy rats was also studied. The animals were followed for 4 weeks. Markers of dehydration and renal damage were evaluated at the end of the study. Fluid restriction and water hydration mildly increased urine osmolality and induced a 15% fall in CrCl while increased the markers of tubular damage by NAG and KIM-1. Such changes were in association with a mild overexpression of V1a and V2 renal receptors, polyol fructokinase pathway overactivation, and increased renal oxidative stress with reduced expression of antioxidant enzymes. Hydration with SB significantly amplified those alterations, while in stevia hydrated rats, the changes were similar to the ones observed in water hydrated rats. These data suggest that current habits of hydration could be a risk factor in developing kidney damage.

Restricted Water Intake and Hydration with Fructose-Containing Beverages during Infancy Predispose to Aggravate an Acute Renal Ischemic Insult in Adolescent Rats.

We aimed to investigate the effects of chronic fluid restriction and hydration with a sweetened beverage (SB) in rats from weaning until adolescence, in a posterior acute kidney injury (AKI) event induced by ischemia-reperfusion (I/R). We followed 5 groups of weaning rats: control group (C); two groups with 22 h/day fluid restriction, a group hydrated for two hours with water (-W) and a group hydrated with SB; one group receiving SB ad libitum all day (+SB); and one group in which water consumption was increased using a gel diet. The rats that reached adolescence were submitted to I/R. Fluid restriction and/or SB hydration induced mild renal alterations that were significantly accentuated in the -SB group and resulted in worse outcomes after I/R-induced AKI that resulted in a catastrophic fall in creatinine clearance and diffuse acute tubular necrosis. In summary, low tap water intakes, as well as SB intake in infancy, prompt kidney worse outcomes in a later event of AKI during adolescence and both insults magnify kidney damage. Studies on hydration habits in children are recommended to disclose the potentially harmful effects that those behavioral patterns might carry to future renal health.

Allopurinol Prevents the Lipogenic Response Induced by an Acute Oral Fructose Challenge in Short-Term Fructose Fed Rats.

We investigated whether short term high fructose intake may induce early hepatic dysfunction in rats and to test whether allopurinol treatment may have beneficial effects. Twenty male Sprague-Dawley rats received 20% fructose in drinking water (10 treated with allopurinol and 10 received vehicle) and 10 control rats received tap water. After 14 days, the hepatic response to an acute fructose load was evaluated, and in fasted animals, respirometry studies in freshly isolated mitochondria were performed. In fasting rats, we did not find differences in systemic or hepatic uric acid and triglyceride concentrations among the groups, but mitochondrial respiratory control rate was significantly decreased by high fructose feeding and correlated with a reduced expression of Complex I, as well as decreased aconitase-2 activity. On the other hand, in fructose fed rats, an acute fructose load increased systemic and hepatic uric acid, triglycerides and oxidative stress. Fructose feeding was also associated with fructokinase and xanthine oxidase overexpression and increased liver de novo lipogenesis program (fatty acid synthase (FAS) and cell death-inducing DFFA-like effector C (CIDEC) overexpression, ATP citrate lyase (ACL) and acetyl coA carboxylase (ACC) overactivity and decreased AMP-activated protein kinase (AMPk) and endothelial nitric oxide synthase (eNOS) activation). Allopurinol treatment prevented hepatic and systemic alterations. These data suggest that early treatment with xanthine oxidase inhibitors might provide a therapeutic advantage by delaying or even halting the progression of non-alcoholic fatty liver disease (NAFLD).

Antioxidant supplements as a novel mean for blocking recurrent heat stress-induced kidney damage following rehydration with fructose-containing beverages.

Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well.

Probiotic supplements prevented oxonic acid-induced hyperuricemia and renal damage.

Hyperuricemia is highly prevalent and especially common in subjects with metabolic, cardiovascular and renal diseases. In chronic kidney disease, hyperuricemia is extremely common, and uric acid (UA) excretion relies on gut uricolysis by gut microbiota. Current therapy for lowering serum UA includes drugs that may produce undesired secondary effects. Therefore, this pilot study was designed to evaluate the potential of two probiotic supplements to reduce systemic uric acid concentrations. Secondary objectives were to assess whether the hypouricemic effect related to a therapeutic benefit on the hyperuricemia-induced renal damage and hypertension. Analysis of fecal microbiota was also performed. Groups of 6 rats each were followed for 5 weeks and allocated in the following treatment groups: C = Control; HU-ND = Oxonic acid-induced hyperuricemia (HU) +regular diet; HU-P = HU+placebo; HU-F1 = HU+ probiotics formula 1 and HU-F2 = HU+ probiotics formula 2. We confirmed that oxonic acid-induced hyperuricemia produced hypertension and renal functional and structural changes, along with modest changes in the overall composition of fecal microbiota. Both probiotic-containing diets prevented HU, elevated UA urinary excretion and intrarenal UA accumulation induced by oxonic acid. The hypouricemic effect conferred by probiotic supplementation also prevented the renal changes and hypertension caused by hyperuricemia. However, probiotic treatment did not restore the fecal microbiota. In conclusion, we demonstrated for the first time the ability of probiotics containing uricolytic bacteria to lower serum uric acid in hyperuricemic animals with beneficial consequences on blood pressure and renal disease. As probiotics supplements are innocuous for human health, we recommend clinical studies to test if probiotic supplements could benefit hyperuricemic individuals.