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Preeclampsia is a hypertensive disorder of pregnancy and is due to abnormal placentation. The pathogenesis remains unclear. Fructose is biologically distinct from glucose and has a critical role in fetal growth in early pregnancy. Many species, including humans, produce fructose in their placenta during the first trimester to assist fetal growth and survival during a time when hypoxia is significant. Fructose is preferred over glucose in hypoxic tissues, and in the developing fetus, fructose has a critical role in stimulating the production of nucleic acids, lipids and glycosaminoglycans. Fructose production normally decreases significantly following the establishment of maternal-fetal circulation following placentation. However, if there is impaired placentation, local hypoxia will continue to drive fructose production. Excessive fructose metabolism drives endothelial dysfunction, oxidative stress, elevated blood pressure, insulin resistance, fatty liver, and a rise in uric acid and vasopressin levels, all of which are features of the preeclamptic state. In addition to fructose production, dietary fructose, for example, from soft drinks, would be additive and has been reported to be a strong independent risk factor for preeclampsia. Uric acid-associated endothelial dysfunction disturbs the invasion of the spiral artery, leading to placental ischemia and further placental hypoxia. Here, we summarize the previous literature regarding the physiological and pathological roles of fructose in pregnancy and propose studies to further investigate the pathogenesis of preeclampsia. Fructose might be a Clue to the Origin of Preeclampsia Insights from Nature and Evolution Preeclampsia is a hypertensive disorder of pregnancy. The pathogenesis remains unclear. Fructose has a critical role in fetal growth in early pregnancy, and might be a key role to developing preeclampsia. Here, we summarize the previous literatures regarding the physiological andpathological roles of fructose in pregnancy to propose studies to further investigate the pathogenesis of preeclampsia.

Umami refers to the savoury taste that is mediated by monosodium glutamate (MSG) and enhanced by inosine monophosphate and other nucleotides. Umami foods have been suggested to increase the risk for obesity and metabolic syndrome but the mechanism is not understood. Here we show that MSG induces obesity, hypothalamic inflammation and central leptin resistance in male mice through the induction of AMP deaminase 2 and purine degradation. Mice lacking AMP deaminase 2 in both hepatocytes and neurons are protected from MSG-induced metabolic syndrome. This protection can be overcome by supplementation with inosine monophosphate, most probably owing to its degradation to uric acid as the effect can be blocked with allopurinol. Thus, umami foods induce obesity and metabolic syndrome by engaging the same purine nucleotide degradation pathway that is also activated by fructose and salt consumption. We suggest that the three tastes—sweet, salt and umami—developed to encourage food intake to facilitate energy storage and survival but drive obesity and diabetes in the setting of excess intake through similar mechanisms.

Climate change should be of special concern for the nephrologist, as the kidney has a critical role in protecting the host from dehydration, but it is also a favorite target of heat stress and dehydration. Here we discuss how rising temperatures and extreme heat events may affect the kidney. The most severe presentation of heat stress is heat stroke, which can result in severe electrolyte disturbance and both acute and chronic kidney disease (CKD). However, lesser levels of heat stress also have multiple effects, including exacerbating kidney disease and precipitating cardiovascular events in subjects with established kidney disease. Heat stress can also increase the risk for kidney stones, cause multiple electrolyte abnormalities and induce both acute and chronic kidney disease. Recently there have been multiple epidemics of CKD of uncertain etiology in various regions of the world, including Mesoamerica, Sri Lanka, India and Thailand. There is increasing evidence that climate change and heat stress may play a contributory role in these conditions, although other causes, including toxins, could also be involved. As climate change worsens, the nephrologist should prepare for an increase in diseases associated with heat stress and dehydration.

Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.

Kidney disease, especially when it is associated with a reduction in estimated glomerular filtration rate, can be associated with an increase in serum urate (uric acid), suggesting that hyperuricemia in subjects with kidney disease may be a strictly secondary phenomenon. Mendelian randomization studies that evaluate genetic scores regulating serum urate also generally have not found evidence that serum urate is a causal risk factor in chronic kidney disease. Nevertheless, this is countered by a large number of epidemiologic, experimental, and clinical studies that have suggested a potentially important role for uric acid in kidney disease and cardiovascular disease. Here, we review the topic in detail. Overall, the studies strongly suggest that hyperuricemia does have an important pathogenic role that likely is driven by intracellular urate levels. An exception may be the role of extracellular uric acid in atherosclerosis and vascular calcification. One of the more striking findings on reviewing the literature is that the primary benefit of lowering serum urate in subjects with CKD is not by slowing the progression of renal disease, but rather by reducing the incidence of cardiovascular events and mortality. We recommend large-scale clinical trials to determine if there is a benefit in lowering serum urate in hyperuricemic subjects in acute and chronic kidney disease and in the reduction of cardiovascular morbidity and mortality in subjects with end-stage chronic kidney disease.

Intake of sugars, especially the fructose component, is strongly associated with the development of obesity and metabolic syndrome, but the relative role of taste versus metabolism in driving preference, intake, and metabolic outcome is not fully understood. We aimed to evaluate the preference for sweet substances and the tendency to develop metabolic syndrome in response to these sugars in mice lacking functional taste signaling [P2X2 (P2X purinoreceptor 2)/P2X3 (P2X purinoreceptor 3) double knockout mice (DKO)] and mice unable to metabolize fructose (fructokinase knockout mice). Of interest, our data indicate that despite their inability to taste sweetness, P2X2/3 DKO mice still prefer caloric sugars (including fructose and glucose) to water in long-term testing, although with diminished preference compared with control mice. Despite reduced intake of caloric sugars by P2X2/3 DKO animals, the DKO mice still show increased levels of the sugar-dependent hormone FGF21 (fibroblast growth factor 21) in plasma and liver. Despite lower sugar intake, taste-blind mice develop severe features of metabolic syndrome due to reduced sensitivity to leptin, reduced ability to mobilize and oxidize fats, and increased hepatic de novo lipogenesis. In contrast to P2X2/3 DKO and wild-type mice, fructokinase knockout mice, which cannot metabolize fructose and are protected against fructose-induced metabolic syndrome, demonstrate reduced preference and intake for all fructose-containing sugars tested but not for glucose or artificial sweeteners. Based on these observations, we conclude that sugar can induce metabolic syndrome in mice independently of its sweet properties. Furthermore, our data demonstrate that the metabolism of fructose is necessary for sugar to drive intake and preference in mice.

We report a case of a patient who developed dialysis-requiring acute kidney injury (AKI) after the use of canagliflozin. A 66-year-old man with type 2 diabetes who was recovering from left knee septic arthritis at a rehabilitation facility was admitted with oliguric AKI 5 days after starting treatment with canagliflozin, an inhibitor of sodium/glucose cotransporter 2 (SGLT2). The patient presented with hematuria, non-nephrotic-range proteinuria, and serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL. There was no recent use of radiocontrast agents or exposure to other nephrotoxins. The patient subsequently required hemodialysis. Due to recent antibiotic use (ampicillin-sulbactam), acute interstitial nephritis was considered in the differential diagnosis. Kidney biopsy was performed, which showed the presence of osmotic nephropathy. The patient's kidney function returned to baseline after 2 weeks of hemodialysis. This case provides evidence of an association of osmotic nephropathy with the use of canagliflozin and discusses potential mechanisms. We recommend kidney biopsy for cases of severe AKI associated with SGLT2 inhibitors to better understand the relationship of this complication with the use of this class of medications.

Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.

Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

Obesity and metabolic syndrome are well-known risk factors for chronic kidney disease (CKD); however, less is known about the mechanism(s) by which metabolic syndrome might accelerate kidney disease. We hypothesized that metabolic syndrome should accelerate the development of kidney disease and that it might be associated with alterations in energy metabolism. We studied the pound mouse (which develops early metabolic syndrome due to a leptin receptor deletion) and wild-type littermates and compared the level of renal injury and muscle wasting after equivalent injury with oral adenine. Renal function, histology, and biochemical analyses were performed. The presence of metabolic syndrome was associated with earlier development of renal disease (12 mo) and earlier mortality in pound mice compared with controls. After administration of adenine, kidney disease was worse in pound mice, and this was associated with greater tubular injury with a decrease in kidney mitochondria, lower tissue ATP levels, and worse oxidative stress. Pound mice with similar levels of renal function as adenine-treated wild-type mice also showed worse sarcopenia, with lower tissue ATP and intracellular phosphate levels. In summary, our data demonstrate that obesity and metabolic syndrome accelerate the progression of CKD and worsen CKD-dependent sarcopenia. Both conditions are associated with renal alterations in energy metabolism and lower tissue ATP levels secondary to mitochondrial dysfunction and reduced mitochondrial number.

Purpose of review Excessive sugar and particularly fructose consumption has been proposed to be a key player in the pathogenesis of metabolic syndrome and kidney disease in humans and animal models. However, besides its dietary source, fructose can be endogenously produced in the body from glucose via the activation of the polyol pathway. In this review, we aim to describe the most recent findings and current knowledge on the potential role of endogenous fructose production and metabolism in disease. Recent findings Over the recent years, the activation of the polyol pathway and endogenous fructose production has been observed in multiple tissues including the liver, renal cortex, and hypothalamic areas of the brain. The activation occurs during the development and progression of metabolic syndrome and kidney disease and results from different stimuli including osmotic effects, diabetes, and ischemia. Even though the potential toxicity of the activation of the polyol pathway can be attributed to several intermediate products, the blockade of endogenous fructose metabolism either by using fructokinase deficient mice or specific inhibitors resulted in marked amelioration of multiple metabolic diseases. Summary New findings suggest that fructose can be produced in the body and that the blockade of tis metabolism could be clinically relevant for the prevention and treatment of metabolic syndrome and kidney disease.

In this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago, were individually and then collectively adaptive for ancestral humans during periods of starvation, but are maladaptive in modern civilization (i.e., “thrifty genes”), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 million years ago enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, which was a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase (ADH4) ~10 million years ago resulted in a remarkable 40-fold increase in the capacity to oxidize ethanol, which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the ethanol ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during ethanol metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to generate more fat, primarily from fructose, to survive changing habitats due to the Middle Miocene disruption and also during the late-Miocene aridification of East Africa. Unfortunately, the enhanced ability to metabolize and utilize ethanol may now be acting to increase our risk for alcoholism, which may be yet another consequence of once-adaptive thrifty genes.

Background: Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD) and unlike many glomerular conditions, it is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation is known to release surfactants in the blood that can bind SIRPα, which is expressed by podocytes and regulates integrin signaling. We performed studies to determine if surfactant-SIRPα interactions may be occurring in MCD. Methods: Studies included developing a novel model of proteinuria by nasal instillation of toll-like receptor ligands (lipopolysaccharide -LPS- and polyinosinic:polycytidylic acid -Poly:IC-), evaluation of serum and urine from 17 children with SSNS/MCD in relapse or remission, and studies using cultured human podocytes treated with sera from children with MCD in remission or relapse. Results: Children with active SSNS/MCD had elevated surfactant proteins A and D in their sera and elevated urinary SIRPα levels, and both decreased when the subjects were in remission. Sera from subjects with SSNS/MCD in relapse, but not in remission, could activate podocyte SIRPα in vitro , leading to release of Src homology 2 domain containing protein tyrosine phosphatase (SHP-2) and Nephrin dephosphorylation thus leading to the activation of the podocyte. The addition of surfactant protein A to MCD sera from a patient in remission could replicate these findings. Similar data was found in mice with nasal instillation of toll-like receptor 4 and 3 agonists LPS and polyI:C which resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Summary: Our data documents a novel pulmonary-podocyte signaling pathway involving surfactants, SIRPα, SHP-2 and Nephrin dephosphorylation in childhood SSNS/MCD.

Objective This study was conducted to identify whether higher fasting blood glucose levels is predictive of hypertension by a large-scale longitudinal design. Methods We conducted a retrospective 5-year cohort study using the data from 13 201 Japanese individuals who underwent annual medical examinations in 2004 and were reevaluated 5 years later. This study included individuals without diabetes or hypertension between ages 30 and 85 years in 2004. The cumulative incidences of hypertension over 5 years in each 10 mg/dl of fasting blood glucose levels were calculated. Moreover, we examined risk factors and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, BMI, smoking and drinking habits, dyslipidemia, chronic kidney disease, serum uric acid, and fasting blood glucose levels by logistic regression analyses. Results We analyzed 10 157 participants (age: 48.9 ± 10.7 years; 43.4% men) without diabetes or hypertension in 2004. After multiple adjustments, higher baseline blood glucose level is an independent risk for hypertension (OR: 1.176; 95% CI 1.086-1.275), as well as aging, women, higher BMI, drinking habits, and higher serum uric acid. After stratifying by sex, higher baseline blood glucose level is an independent risk for hypertension both in women (OR: 1.295; 95% CI 1.135-1.478) and men (OR: 1.108; 95% CI 1.001-1.227). When we conducted the same analysis using glycated hemoglobin instead of blood glucose, glycated hemoglobin was not a risk for hypertension. Conclusion Higher fasting blood glucose is an independent risk for developing hypertension. Further studies are needed to determine if treatment for elevated blood glucose can prevent developing hypertension.

The potential contribution of serum osmolarity in the modulation of blood pressure has not been evaluated. This study was done to examine the relationship between hyperosmolarity and hypertension in a five-year longitudinal design. We enrolled 10,157 normotensive subjects without diabetes who developed hypertension subsequently as determined by annual medical examination in St. Luke&rsquo, s International Hospital, Tokyo, between 2004 and 2009. High salt intake was defined as &gt, 12 g/day by a self-answered questionnaire and hyperosmolarity was defined as &gt, 293 mOsm/L serum osmolarity, calculated using serum sodium, fasting blood glucose, and blood urea nitrogen. Statistical analyses included adjustments for age, gender, body mass index, smoking, drinking alcohol, dyslipidemia, hyperuricemia, and chronic kidney disease. In the patients with normal osmolarity, the group with high salt intake had a higher cumulative incidence of hypertension than the group with normal salt intake (8.4% versus 6.7%, p = 0.023). In contrast, in the patients with high osmolarity, the cumulative incidence of hypertension was similar in the group with high salt intake and in the group with normal salt intake (13.1% versus 12.9%, p = 0.84). The patients with hyperosmolarity had a higher incidence of hypertension over five years compared to that of the normal osmolarity group (p &lt, 0.001). After multiple adjustments, elevated osmolarity was an independent risk for developing hypertension (OR (odds ratio), 1.025, 95% CI (confidence interval), 1.006&ndash, 1.044), regardless of the amount of salt intake. When analyzed in relation to each element of calculated osmolarity, serum sodium and fasting blood glucose were independent risks for developing hypertension. Our results suggest that hyperosmolarity is a risk for developing hypertension regardless of salt intake.

Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase–fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

Objective Whether obesity without metabolic syndrome (i.e., “metabolically healthy” obesity) confers similar or less metabolic risk remains controversial. Methods A retrospective 5-year cohort study of 9,721 Japanese subjects (48.5 ± 10.5 years, 4,160 men) was conducted in 2004 and reevaluated 5 years later. Subjects were excluded if they were hypertensive or diabetic or were receiving medications for dyslipidemia and/or gout or hyperuricemia in 2004. Study subjects were categorized according to baseline BMI ≥ 25 kg/m2 (overweight/obesity) and

Although it is well established that acute kidney injury (AKI) is a proinflammatory state, little is known about the endogenous counter-inflammatory response. IL-6 is traditionally considered a pro-inflammatory cytokine that is elevated in the serum in both human and murine AKI. However, IL-6 is known to have anti-inflammatory effects. Here we sought to investigate the role of IL-6 in the counter-inflammatory response after AKI, particularly in regard to the anti-inflammatory cytokine IL-10. Ischemic AKI was induced by bilateral renal pedicle clamping. IL-10–deficient mice had increased systemic and lung inflammation after AKI, demonstrating the role of IL-10 in limiting inflammation after AKI. We then sought to determine whether IL-6 mediates IL-10 production. Wild-type mice with AKI had a marked upregulation of splenic IL-10 that was absent in IL-6–deficient mice with AKI. In vitro , addition of IL-6 to splenocytes increased IL-10 production in CD4 + T cells, B cells, and macrophages. In vivo , CD4-deficient mice with AKI had reduced splenic IL-10 and increased lung myeloperoxidase activity. Thus, IL-6 directly increases IL-10 production and participates in the counter-inflammatory response after AKI.

The optimal range of serum uric acid (urate) associated with the lowest risk for developing cardiometabolic diseases is unknown in a generally healthy population. This 5-year cohort study is designed to identify the optimal range of serum urate. The data were collected from 13,070 Japanese between ages 30 and 85 at the baseline (2004) from the Center for Preventive Medicine, St. Luke&rsquo, s International Hospital, Tokyo. We evaluated the number of subjects (and prevalence) of those free of the following conditions: hypertension, diabetes, dyslipidemia, and chronic kidney disease (CKD) over 5 years for each 1 mg/dL of serum urate stratified by sex. Furthermore, the odds ratios (ORs) for remaining free of these conditions were calculated with multiple adjustments. Except for truly hypouricemic subjects, having lower serum urate was an independent factor for predicting the absence of hypertension, dyslipidemia, and CKD, but not diabetes. The OR of each 1 mg/dL serum urate decrease as a protective factor for hypertension, dyslipidemia, and CKD was 1.153 (95% confidence interval, 1.068&ndash, 1.245), 1.164 (1.077&ndash, 1.258), and 1.226 (1.152&ndash, 1.306) in men, 1.306 (1.169&ndash, 1.459), 1.121 (1.022&ndash, 1.230), and 1.424 (1.311&ndash, 1.547) in women, respectively. Moreover, comparing serum urate of 3&ndash, 5 mg/dL in men and 2&ndash, 4 mg/dL in women, hypouricemia could be a higher risk for developing hypertension (OR: 4.532, 0.943&ndash, 21.78) and CKD (OR: 4.052, 1.181&ndash, 13.90) in women, but not in men. The optimal serum urate range associated with the lowest development of cardiometabolic diseases was less than 5 mg/dL for men and 2&ndash, 4 mg/dL for women, respectively.

Umami refers to the savoury taste that is mediated by monosodium glutamate (MSG) and enhanced by inosine monophosphate and other nucleotides. Umami foods have been suggested to increase the risk for obesity and metabolic syndrome but the mechanism is not understood. Here we show that MSG induces obesity, hypothalamic inflammation and central leptin resistance in male mice through the induction of AMP deaminase 2 and purine degradation. Mice lacking AMP deaminase 2 in both hepatocytes and neurons are protected from MSG-induced metabolic syndrome. This protection can be overcome by supplementation with inosine monophosphate, most probably owing to its degradation to uric acid as the effect can be blocked with allopurinol. Thus, umami foods induce obesity and metabolic syndrome by engaging the same purine nucleotide degradation pathway that is also activated by fructose and salt consumption. We suggest that the three tastes-sweet, salt and umami-developed to encourage food intake to facilitate energy storage and survival but drive obesity and diabetes in the setting of excess intake through similar mechanisms.

An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria ( R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.

Background: the consumption of sweetened beverages is associated with increased risk of metabolic syndrome, cardiovascular disease, and type 2 diabetes mellitus. Objective: we hypothesized that the metabolic effects of fructose in sugary beverages might be modulated by the speed of ingestion in addition to the overall amount. Design: thirty healthy subjects free of any disease and medication were recruited into two groups. After overnight fasting, subjects in group 1 drank 500 mL of apple juice over an hour by drinking 125 mL every 15 min, while subjects in group 2 drank 500 mL of apple juice over 5 min. Blood samples were collected at time zero and 15, 30, 60, and 120 min after ingestion to be analyzed for serum glucose, insulin, homeostatic model assessment (HOMA-IR) score, fibroblast growth factor 21, copeptin, osmolarity, sodium, blood urea nitrogen (BUN), lactate, uric acid, and phosphate levels. Results: serum glucose, insulin, HOMA-IR, fibroblast growth factor 21, copeptin, osmolarity, sodium, BUN, and lactate levels increased following apple juice ingestion. The increases were greater in the fast-drinking group, which were more significant after 15 min and 30 min compared to baseline. The changes in uric acid were not statistically different between the groups. Phosphate levels significantly increased only in the fast-drinking group. Conclusion: fast ingestion of 100% apple juice causes a significantly greater metabolic response, which may be associated with negative long-term outcomes. Our findings suggest that the rate of ingestion must be considered when evaluating the metabolic impacts of sweetened beverage consumption., NIH

Metabolic syndrome and diabetes are main health problems of modern life in the twenty-first century. Alarming ratios of global prevalence lead to conduct more and more researches about etiological factors and pathogenesis. Disease mechanism is elementary for advancing more efficient and practicable treatment methods. Concurrent increase in both fructose consumption with Western diet and metabolic syndrome has revealed fructose hypothesis that suggests fructose as one of etiological factor of metabolic syndrome (insulin resistance, central obesity, hypertension, etc.). Recent studies have increasingly lightened the unknowns about role of fructose on pathogenesis. This review discusses fructose hypothesis by exploring current studies and their results in wide perspective. Potential mechanisms covering low-grade inflammation or de novo lipogenesis, etc., in the development of insulin resistance and obesity are explained. Clinical trials have revealed connection of fructose-induced hyperuricemia with insulin resistance and chronic inflammatory state leading to hepatosteatosis or obesity. Further, novel hypothesizes suggesting role of fructose-induced modifications in epigenetics, gut microbiota and oxidative stress on disease pathogenesis are reviewed based on recent clinical trials. More innovative theories including fructose-induced malignancy; decreased satiety feeling, and unfavorable bone health are argued covering fructose-induced neurotransmitter changes in central nervous system, more aggressive malignancy phenotype and impaired calcium absorption.

Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease.

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (

Injectable hydrogels can be used to deliver drugs in situ over a sustained period of time. We hypothesized that sustained delivery of interleukin-10 (IL-10) following acute kidney injury (AKI) would mitigate the local and systemic proinflammatory cascade induced by AKI and reduce subsequent fibrosis. Wild-type C57BL/6 mice underwent ischemia-reperfusion AKI with avertin anesthesia. Three days later, mice were treated with either hyaluronic acid injectable hydrogel with or without IL-10, or IL-10 suspended in saline, injected under the capsule of the left kidney, or hydrogel with IL-10 injected subcutaneously. Untreated AKI served as controls. Serial in vivo optical imaging tracked the location and degradation of the hydrogel over time. Kidney function was assessed serially. Animals were killed 28 days following AKI and the following were evaluated: serum IL-6, lung inflammation, urine neutrophil gelatinase-associated lipocalin, and renal histology for fibroblast activity, collagen type III deposition and fibrosis via Picrosirius Red staining and second harmonic imaging. Our model shows persistent systemic inflammation, and renal inflammation and fibrosis 28 days following AKI. The hydrogels are biocompatible and reduced serum IL-6 and renal collagen type III 28 days following AKI even when delivered without IL-10. Treatment with IL-10 reduced renal and systemic inflammation, regardless of whether the IL-10 was delivered in a sustained manner via the injectable hydrogel under the left kidney capsule, as a bolus injection via saline under the left kidney capsule, or via the injectable hydrogel subcutaneously. Injectable hydrogels are suitable for local drug delivery following renal injury, are biocompatible, and help mitigate local and systemic inflammation.

Climate change has led to significant rise of 0.8°C–0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves (extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions.

Intake of fructose-containing sugars is strongly associated with metabolic syndrome. Compared with other sugars, dietary fructose is uniquely metabolized by fructokinase. However, the tissue-specific role of fructokinase in sugar-induced metabolic syndrome, and the specific roles of glucose and fructose in driving it, is not fully understood. Here, we show that in mice receiving excess fructose-glucose solutions, whole-body deletion of fructokinase, and thus full blockade of fructose metabolism, is sufficient to prevent metabolic syndrome. This protection is not only due to reduced fructose metabolism, but also due to decreased sugar intake. Furthermore, by using tissue-specific fructokinase-deficient mice, we determined that while sugar intake is controlled by intestinal fructokinase activity, metabolic syndrome is driven by fructose metabolism in the liver. Our findings show a two-pronged role for fructose metabolism in sugar-induced metabolic syndrome, one arm via the intestine that mediates sugar intake and a second arm in the liver that drives metabolic dysfunction.

Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that fructose also can be produced via the polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover, fructose metabolism yields uric acid, which is highly associated with NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether uric acid regulates aldose reductase, a key enzyme in the polyol pathway. We evaluated whether soluble uric acid regulates aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous fructose production and fat accumulation. Uric acid dose-dependently stimulated aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous fructose production and triglyceride accumulation. This stimulatory mechanism was mediated by uric acid-induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5). Uric acid also amplified the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic aldose reductase expression, endogenous fructose accumulation, and fat buildup that was significantly reduced by co-administration of the xanthine oxidase inhibitor allopurinol. These results suggest that uric acid generated during fructose metabolism may act as a positive feedback mechanism that stimulates endogenous fructose production by stimulating aldose reductase in the polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in glucose and fructose can induce NAFLD.