RESUMO
BACKGROUND: Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body's cellular response to a hot environment. OBJECTIVE: This longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. METHODS: We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. RESULTS: At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (ß: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. CONCLUSIONS: These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.
Assuntos
Biomarcadores , Fazendeiros , Proteínas de Choque Térmico HSP70 , Temperatura Alta , Exposição Ocupacional , Humanos , Proteínas de Choque Térmico HSP70/imunologia , Proteínas de Choque Térmico HSP70/sangue , Estudos Longitudinais , Masculino , Biomarcadores/sangue , Adulto , Feminino , Exposição Ocupacional/efeitos adversos , Temperatura Alta/efeitos adversos , Pessoa de Meia-Idade , Guatemala , Rim , Agricultura , Anticorpos/sangue , Transtornos de Estresse por Calor , UmidadeRESUMO
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.
Assuntos
Transtornos de Estresse por Calor , Nefrologia , Insuficiência Renal Crônica , Humanos , Mudança Climática , Desidratação/complicações , Insuficiência Renal Crônica/complicações , Rim , Transtornos de Estresse por Calor/complicaçõesRESUMO
Cardiorenal syndrome type 4 (CRS type 4) occurs when chronic kidney disease (CKD) leads to cardiovascular damage, resulting in high morbidity and mortality rates. Mitochondria, vital organelles responsible for essential cellular functions, can become dysfunctional in CKD. This dysfunction can trigger inflammatory responses in distant organs by releasing Damage-associated molecular patterns (DAMPs). These DAMPs are recognized by immune receptors within cells, including Toll-like receptors (TLR) like TLR2, TLR4, and TLR9, the nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing-3 (NLRP3) inflammasome, and the cyclic guanosine monophosphate (cGMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (cGAS-STING) pathway. Activation of these immune receptors leads to the increased expression of cytokines and chemokines. Excessive chemokine stimulation results in the recruitment of inflammatory cells into tissues, causing chronic damage. Experimental studies have demonstrated that chemokines are upregulated in the heart during CKD, contributing to CRS type 4. Conversely, chemokine inhibitors have been shown to reduce chronic inflammation and prevent cardiorenal impairment. However, the molecular connection between mitochondrial DAMPs and inflammatory pathways responsible for chemokine overactivation in CRS type 4 has not been explored. In this review, we delve into mechanistic insights and discuss how various mitochondrial DAMPs released by the kidney during CKD can activate TLRs, NLRP3, and cGAS-STING immune pathways in the heart. This activation leads to the upregulation of chemokines, ultimately culminating in the establishment of CRS type 4. Furthermore, we propose using chemokine inhibitors as potential strategies for preventing CRS type 4.
Assuntos
Síndrome Cardiorrenal , Insuficiência Renal Crônica , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Mitocôndrias/metabolismo , Nucleotidiltransferases/metabolismo , Receptores Imunológicos/metabolismo , Alarminas/metabolismo , Quimiocinas/metabolismo , Insuficiência Renal Crônica/metabolismoRESUMO
Hyperuricemia predicts the development of chronic kidney disease (CKD) and metabolic complications, but whether it has a causal role has been controversial. This is especially true given the 2 recently conducted randomized controlled trials that failed to show a benefit of lowering uric acid in type 1 diabetes-associated CKD and subjects with stage 3-4 CKD. While these studies suggest that use of urate-lowering drugs in unselected patients is unlikely to slow the progression of CKD, there are subsets of subjects with CKD where reducing uric acid synthesis may be beneficial. This may be the case in patients with gout, hyperuricemia (especially associated with increased production), and urate crystalluria. Here, we discuss the evidence and propose that future clinical trials targeting these specific subgroups should be performed.
Assuntos
Hiperuricemia/complicações , Insuficiência Renal Crônica/etiologia , Humanos , Hiperuricemia/tratamento farmacológico , Insuficiência Renal Crônica/prevenção & controleRESUMO
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.
Assuntos
Cumarínicos/farmacologia , Dieta Ocidental/efeitos adversos , Frutoquinases/antagonistas & inibidores , Nefropatias/prevenção & controle , Síndrome Metabólica/prevenção & controle , Animais , Cumarínicos/uso terapêutico , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Frutoquinases/metabolismo , Frutose/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos WistarRESUMO
BACKGROUND: Vasopressin is elevated in response to heat and dehydration and has been postulated to have a role in the chronic kidney disease of unknown origin being observed in Central America. The aims of this study were to examine whether the vasopressin pathway, as measured by copeptin, is associated with the presence of kidney dysfunction, and to examine whether higher fluid intake is associated with lower circulating copeptin and thereby preserves kidney health among sugarcane workers exposed to hot conditions. METHODS: Utilizing a longitudinal study of 105 workers in Guatemala, we examined relationships between hydration indices, plasma copeptin concentrations, and kidney function markers at 3 times during the 6-month harvest. We also examined whether baseline copeptin concentrations increased the odds of developing an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. RESULTS: Copeptin concentrations were positively associated with serum creatinine (ß 1.41, 95% CI 0.88-2.03) and negatively associated with eGFR (ß -1.07, 95% CI -1.43 to -0.70). In addition, as workers improved their hydration (measured by increases in fluid balance), copeptin concentrations were reduced, and this reduction was associated with an improvement in kidney function. CONCLUSIONS: Results suggest that copeptin should be studied as a potential prognostic biomarker.
Assuntos
Doenças dos Trabalhadores Agrícolas/diagnóstico , Desidratação/diagnóstico , Glicopeptídeos/sangue , Neurofisinas/sangue , Precursores de Proteínas/sangue , Insuficiência Renal Crônica/diagnóstico , Vasopressinas/sangue , Adulto , Doenças dos Trabalhadores Agrícolas/epidemiologia , Doenças dos Trabalhadores Agrícolas/etiologia , Biomarcadores/sangue , Desidratação/sangue , Desidratação/complicações , Desidratação/epidemiologia , Guatemala/epidemiologia , Temperatura Alta/efeitos adversos , Humanos , Rim/fisiopatologia , Testes de Função Renal , Estudos Longitudinais , Masculino , Exposição Ocupacional/efeitos adversos , Prevalência , Prognóstico , Estudos Prospectivos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , SaccharumRESUMO
Five-sixths nephrectomy (5/6Nx) model is widely used for studying the mechanisms involved in chronic kidney disease (CKD) progression, a kidney pathology that has increased dramatically in recent years. Mitochondrial impairment is a key mechanism that aggravates CKD progression; however, the information on mitochondrial bioenergetics and redox alterations along a time course in a 5/6Nx model is still limited and in some cases contradictory. Therefore, we performed for the first time a time-course study of mitochondrial alterations by high-resolution respirometry in the 5/6Nx model. Our results show a decrease in mitochondrial ß-oxidation at early times, as well as a permanent impairment in adenosine triphosphate (ATP) production in CI-linked respiration, a permanent oxidative state in mitochondria and decoupling of these organelles. These pathological alterations are linked to the early decrease in complex I and ATP synthase activities and to the further decrease in complex III activity. Therefore, our results may suggest that mitochondrial bioenergetics impairment is an early event in renal damage, whose persistence in time aggravates CKD development in the 5/6Nx model.
Assuntos
Mitocôndrias/metabolismo , Nefrectomia/efeitos adversos , Estresse Oxidativo/fisiologia , Insuficiência Renal Crônica , Animais , Progressão da Doença , Metabolismo Energético , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Rim/metabolismo , Rim/patologia , Rim/cirurgia , Masculino , Mitocôndrias/patologia , Nefrectomia/métodos , Oxirredução , Consumo de Oxigênio/fisiologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fatores de TempoRESUMO
An epidemic of chronic kidney disease (CKD) has been observed in Central America among workers in the sugarcane fields. One hypothesis is that the CKD may be caused by recurrent heat stress and dehydration, and potentially by hyperuricemia. Accordingly, we developed a murine model of kidney injury associated with recurrent heat stress. In the current experiment, we tested whether treatment with allopurinol (a xanthine oxidase inhibitor that reduces serum urate) provides renal protection against recurrent heat stress and dehydration. Eight-week-old male C57BL/6 mice were subjected to recurrent heat stress (39.5°C for 30 min, 7 times daily, for 5 wk) with or without allopurinol treatment and were compared with control animals with or without allopurinol treatment. Mice were allowed ad libitum access to normal laboratory chow (Harlan Teklad). Kidney histology, liver histology, and renal function were examined. Heat stress conferred both kidney and liver injury. Kidneys showed loss of proximal tubules, infiltration of monocyte/macrophages, and interstitial collagen deposition, while livers of heat-stressed mice displayed an increase in macrophages, collagen deposition, and myofibroblasts. Allopurinol provided significant protection and improved renal function in the heat-stressed mice. The renal protection was associated with reduction in intrarenal uric acid concentration and heat shock protein 70 expression. Heat stress-induced renal and liver injury can be protected with allopurinol treatment. We recommend a clinical trial of allopurinol for individuals developing renal injury in rural areas of Central America where the epidemic of chronic kidney disease is occurring.
Assuntos
Alopurinol/farmacologia , Inibidores Enzimáticos/farmacologia , Transtornos de Estresse por Calor/prevenção & controle , Temperatura Alta , Hipertermia Induzida , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Proteínas de Choque Térmico HSP70/metabolismo , Transtornos de Estresse por Calor/etiologia , Transtornos de Estresse por Calor/metabolismo , Transtornos de Estresse por Calor/patologia , Rim/metabolismo , Rim/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Ácido Úrico/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismoRESUMO
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.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Alopurinol/administração & dosagem , Resposta ao Choque Térmico , Rabdomiólise/tratamento farmacológico , Bicarbonato de Sódio/efeitos adversos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Glicerol/administração & dosagem , Glicerol/toxicidade , Temperatura Alta/efeitos adversos , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Ácido Oxônico/administração & dosagem , Ratos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/prevenção & controle , Rabdomiólise/sangue , Rabdomiólise/etiologia , Resultado do Tratamento , Urato Oxidase/antagonistas & inibidores , Urato Oxidase/metabolismo , Ácido Úrico/sangue , Ácido Úrico/metabolismoRESUMO
Nowadays, chronic kidney disease (CKD) is considered a worldwide public health problem. CKD is a term used to describe a set of pathologies that structurally and functionally affect the kidney, it is mostly characterized by the progressive loss of kidney function. Current therapeutic approaches are insufficient to avoid the development of this disease, which highlights the necessity of developing new strategies to reverse or at least delay CKD progression. Kidney is highly dependent on mitochondrial homeostasis and function, consequently, the idea that mitochondrial pathologies could play a pivotal role in the genesis and development of kidney diseases has risen. Although many research groups have recently published studies of mitochondrial function in acute kidney disease models, the existing information about CKD is still limited, especially in renal mass reduction (RMR) models. This paper focuses on reviewing current experimental information about the bioenergetics, dynamics (fission and fusion processes), turnover (mitophagy and biogenesis) and redox mitochondrial alterations in RMR, to discuss and integrate the mitochondrial changes triggered by nephron loss, as well as its relationship with loss of kidney function in CKD, in these models. Understanding these mechanisms would allow us to design new therapies that target these mitochondrial alterations.
Assuntos
Mitocôndrias/fisiologia , Insuficiência Renal Crônica/fisiopatologia , Animais , Progressão da Doença , Metabolismo Energético , Humanos , Rim/fisiologia , Renovação Mitocondrial , OxirreduçãoRESUMO
Diabetic nephropathy (DN) is presently the primary cause of chronic kidney disease and end-stage renal disease (ESRD). It has been suggested that inflammation and oxidative stress, in addition to or in concert with the metabolic changes, plays an important role in the maintenance and progression of the disease. Therefore, attenuating or blocking these mechanisms may be a therapeutic target to delay the progression of the disease. Diallyl thiosulfinate (allicin), a compound derived from garlic, inhibits free radical formation, increases glutathione synthesis and decreases the levels of proinflammatory molecules in vitro. This research aimed to assess the effect of allicin on oxidative stress and inflammation-induced diabetes. Animals were divided into control and diabetes (streptozotocin 50 mg/kg i.p.), and maintained for 30 days. After 30 days, the group of diabetic animals was subdivided into diabetes and allicin-treated diabetes (16 mg/kg/day oral gavage). The three experimental groups were maintained for another month. We analyzed the status of renal function, oxidative stress and proinflammatory cytokines. The untreated diabetic group showed hyperglycemia and increased diuresis, creatinine clearance, proteinuria, glycosuria and urinary excretion of N-acetyl-ß-d-glucosaminidase (NAG), as well as increased oxidative stress and the expression of interleukin 1ß (IL-1ß), IL-6, nuclear factor kappa beta (NFκß) and transforming growth factor-ß1 (TGF-ß1) in plasma and kidney. In contrast, the inhibitor of NFκß (Iκß) is decreased in the cortex. It has been demonstrated that the allicin treatment decreases hyperglycemia, polyuria, and NAG excretion. The oxidative stress and proinflammatory cytokines were also reduced by the allicin treatment. In conclusion, allicin delays the progression of diabetic nephropathy through antioxidant and anti-inflammatory mechanisms.
Assuntos
Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/metabolismo , Suplementos Nutricionais , Alho/química , Imunomodulação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ácidos Sulfínicos/farmacologia , Animais , Antioxidantes/farmacologia , Biomarcadores , Glicemia , Creatinina/sangue , Citocinas/sangue , Citocinas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Progressão da Doença , Dissulfetos , Taxa de Filtração Glomerular , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Testes de Função Renal , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Insuficiência Renal Crônica/metabolismoRESUMO
Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. NEW & NOTEWORTHY: This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated.
Assuntos
Desidratação/fisiopatologia , Frutoquinases/deficiência , Frutose/farmacologia , Regulação da Expressão Gênica , Hipotálamo , Vasopressinas/metabolismo , Análise de Variância , Animais , Ensaio de Imunoadsorção Enzimática , Frutoquinases/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Temperatura Alta/efeitos adversos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , RNA Mensageiro/metabolismo , Fatores de Tempo , Vasopressinas/genética , Privação de ÁguaRESUMO
PURPOSE OF REVIEW: Mesoamerican nephropathy (MeN) is an emerging pathophysiological entity of Chronic kidney desease (CKD) not related to traditional risk factors (diabetes and hypertension) that have caused thousands of deaths in Central America, mainly in sugarcane workers. The focus of this review is to discuss the risk factors and probable mechanisms involved in the initiation and progression of this devastating disease. RECENT FINDINGS: Frequent episodes of subclinical Acute kidney injury caused by repetitive heat stress, dehydration, and strenuous work have been regarded as the main risk factors for MeN. The combination of them chronically activates vasopressin, renin angiotensin aldosterone system, and polyol-fructokinase pathway in the kidney. Also, subclinical rhabdomyolysis compound the framework of the disease by exacerbating systemic inflammation and inducing uricosuria. Exposure to nephrotoxins, high fructose intake, and use of NSAIDs could also contribute to further accelerating the progression of the disease. SUMMARY: The evidence supports the notion that recurrent cycles of heat stress, dehydration, and strenuous work may cause CKD. The chronic activation of such mechanisms likely occurs in other conditions of reduced water intake and probably explains why the current management of CKD has not been effective to revert or halt the progression to end-stage CKD.
Assuntos
Injúria Renal Aguda/fisiopatologia , Doenças dos Trabalhadores Agrícolas/fisiopatologia , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Saccharum , Injúria Renal Aguda/etiologia , Doenças dos Trabalhadores Agrícolas/etiologia , Doenças dos Trabalhadores Agrícolas/mortalidade , América Central , Desidratação , Progressão da Doença , Transtornos de Estresse por Calor/etiologia , Transtornos de Estresse por Calor/mortalidade , Transtornos de Estresse por Calor/fisiopatologia , Humanos , Recidiva , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/mortalidade , Fatores de RiscoRESUMO
Recent studies suggest that allicin may play a role in chronic kidney disease (CKD), reducing hypertension and oxidative stress and improving renal dysfunction. In the present study, CKD was induced by 5/6 nephrectomy and the animals were divided into four treatment groups as follows: control (C), CKD, CKD+allicin (40 mg/kg pathway oral) (CKDA), and CKD+Losartan (20 mg/kg) (CKDL). After CKD induction, the rats developed hypertension from week 3 to the end of the study. This was associated with increased creatinine and blood urea nitrogen (BUN) levels in serum, increased albuminuria, increased urinary excretion of N-acetyl-ß-d-glucosaminidase (NAG), increased nephrin expression, and incrased histological alterations in the cortex. The levels of angiotensin receptors and endothelial nitric oxide synthase (eNOS) were decreased in the renal cortex from the CKD group. Otherwise, lipid and protein oxidation were higher in the CKD group than in the control group. A disturbance was observed in the expression levels of the nuclear factor erythroid 2-related factor 2/Kelch ECH associating protein 1 system (Nrf2/keap1) and the antioxidant enzymes catalase, superoxide dismutase, and heme oxygenase-1. Allicin or losartan treatments relieved renal dysfunction, hypertension, and oxidative stress. In addition, both treatments showed the same efficacy on the expression of angiotensin receptors, the nephrin, Nrf2/keap1 pathway, and eNOS. Further in silico analyses suggest that allicin and losartan could have a common mechanism involving interaction with AT1 receptors. Allicin showed antihypertensive, antioxidant, and nephroprotective effects. The beneficial effects showed by allicin are similar, or even better, than those of losartan. In fact, the effect of allicin on blood pressure and renal function is comparable to reductions seen with losartan, a prescription drug commonly used as a first-line therapy.
Assuntos
Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Losartan/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Ácidos Sulfínicos/uso terapêutico , Acetilglucosaminidase/urina , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Creatinina/sangue , Dissulfetos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/metabolismo , Losartan/administração & dosagem , Losartan/efeitos adversos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Ácidos Sulfínicos/administração & dosagem , Ácidos Sulfínicos/efeitos adversos , Ureia/sangueRESUMO
Recurrent dehydration, such as commonly occurs with manual labor in tropical environments, has been recently shown to result in chronic kidney injury, likely through the effects of hyperosmolarity to activate both vasopressin and aldose reductase-fructokinase pathways. The observation that the latter pathway can be directly engaged by simple sugars (glucose and fructose) leads to the hypothesis that soft drinks (which contain these sugars) might worsen rather than benefit dehydration associated kidney disease. Recurrent dehydration was induced in rats by exposure to heat (36°C) for 1 h/24 h followed by access for 2 h to plain water (W), a 11% fructose-glucose solution (FG, same composition as typical soft drinks), or water sweetened with noncaloric stevia (ST). After 4 wk plasma and urine samples were collected, and kidneys were examined for oxidative stress, inflammation, and injury. Recurrent heat-induced dehydration with ad libitum water repletion resulted in plasma and urinary hyperosmolarity with stimulation of the vasopressin (copeptin) levels and resulted in mild tubular injury and renal oxidative stress. Rehydration with 11% FG solution, despite larger total fluid intake, resulted in greater dehydration (higher osmolarity and copeptin levels) and worse renal injury, with activation of aldose reductase and fructokinase, whereas rehydration with stevia water had opposite effects. In animals that are dehydrated, rehydration acutely with soft drinks worsens dehydration and exacerbates dehydration associated renal damage. These studies emphasize the danger of drinking soft drink-like beverages as an attempt to rehydrate following dehydration.
Assuntos
Bebidas Gaseificadas/efeitos adversos , Desidratação/induzido quimicamente , Hidratação/efeitos adversos , Nefropatias/induzido quimicamente , Animais , Pressão Sanguínea/efeitos dos fármacos , Desidratação/complicações , Frutose/farmacologia , Frutose/urina , Glicopeptídeos/sangue , Temperatura Alta/efeitos adversos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/patologia , Testes de Função Renal , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Stevia , Edulcorantes/farmacologia , Ácido Úrico/urina , Água/farmacologia , Equilíbrio HidroeletrolíticoRESUMO
UNLABELLED: Cisplatin (CP) is an antineoplastic agent that induces nephrotoxicity and oxidative stress. It is unknown whether renal tight junction (TJ) proteins expression and localization are modified in CP-induced nephrotoxicity. OBJECTIVE: To study if the expression of the TJ proteins occludin, claudin-2, claudin-5 and zonula occludens-1 (ZO-1) is modified in rats with CP-induced nephrotoxicity. MATERIALS AND METHODS: Male Wistar rats (n = 5/group) were injected with saline solution (V group), and the other group (CP group) was injected with a single dose of saline solution and CP (7.5 mg/kg i.p.). Rats were sacrificed 72 h after CP injection and blood, and 24-h urine samples were collected. Several plasma and urinary injury biomarkers as well as renal histopathology lesions, oxidative and nitrosative stress markers were evaluated, and protein levels of ocludin, claudin-2, claudin-5, ZO-1 were measured by Western blot. Statistically significant changes noted with different p < 0.05 versus V. RESULTS: Nephrotoxicity was evident by histological alterations, glycosuria, decrease in creatinine clearance, increase in fractional excretion of sodium, serum creatinine and kidney injury molecule-1. These changes were associated with oxidative/nitrosative stress (increased renal abundance of 3-nitrotyrosine and protein kinase Cß2 and decreased renal expression of nuclear factor-erythroid-2-related factor 2) and decreased activity of antioxidant enzymes. Finally, it was found that CP-induced renal damage was associated with decreased renal expression of occludin and claudin-2. DISCUSSION AND CONCLUSION: CP altered the TJ proteins expression and localization in the proximal tubule that was associated with oxidative/nitrosative stress.
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Cisplatino/toxicidade , Rim/efeitos dos fármacos , Proteínas/metabolismo , Junções Íntimas/efeitos dos fármacos , Animais , Biomarcadores/sangue , Biomarcadores/urina , Western Blotting , Rim/metabolismo , Masculino , Ratos , Ratos Wistar , Junções Íntimas/metabolismoRESUMO
Diabetes mellitus (DM) is a chronic disease characterized by persistent hyperglycemia, which is a major contributing factor to chronic kidney disease (CKD), end-stage renal disease (ESRD), and cardiovascular-related deaths. There are several mechanisms leading to kidney injury, with hyperglycemia well known to stimulate oxidative stress, inflammation, tissue remodeling, and dysfunction in the vascular system and organs. Increased reactive oxygen species (ROS) decrease the bioavailability of vasodilators while increasing vasoconstrictors, resulting in an imbalance in vascular tone and the development of hypertension. Treatments for diabetes focus on controlling blood glucose levels, but due to the complexity of the disease, multiple drugs are often required to successfully delay the development of microvascular complications, including CKD. In this context, naringenin, a flavonoid found in citrus fruits, has demonstrated anti-inflammatory, anti-fibrotic, and antioxidant effects, suggesting its potential to protect the kidney from deleterious effects of diabetes. This review aims to summarize the scientific evidence of the effects of naringenin as a potential therapeutic option for diabetes-induced CKD.
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Background: Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by high temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body's cellular response to a hot environment. Objective: This longitudinal study investigated the impact of high temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. Methods: We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. Results: At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (ß: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. Conclusions: These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.
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Metabolic syndrome (MetS) is a multifactorial condition that significantly increases the risk of cardiovascular disease and chronic kidney disease (CKD). Recent studies have emphasized the role of lipid dysregulation in activating cellular mechanisms that contribute to CKD progression in the context of MetS. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated efficacy in improving various components of MetS, including obesity, dyslipidemia, and insulin resistance. While SGLT2i have shown cardioprotective benefits, the underlying cellular mechanisms in MetS and CKD remain poorly studied. Therefore, this review aims to elucidate the cellular mechanisms by which SGLT2i modulate lipid metabolism and their impact on insulin resistance, mitochondrial dysfunction, oxidative stress, and CKD progression. We also explore the potential benefits of combining SGLT2i with other antidiabetic drugs. By examining the beneficial effects, molecular targets, and cytoprotective mechanisms of both natural and synthetic SGLT2i, this review provides a comprehensive understanding of their therapeutic potential in managing MetS-induced CKD. The information presented here highlights the significance of SGLT2i in addressing the complex interplay between metabolic dysregulation, lipid metabolism dysfunction, and renal impairment, offering clinicians and researchers a valuable resource for developing improved treatment strategies and personalized approaches for patients with MetS and CKD.
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Releasing unilateral ureteral obstruction (RUUO) is the gold standard for decreasing renal damage induced during unilateral ureteral obstruction (UUO); however, the complete recovery after RUUO depends on factors such as the time and severity of obstruction and kidney contralateral compensatory mechanisms. Interestingly, previous studies have shown that kidney damage markers such as oxidative stress, inflammation, and apoptosis are present and even increase after removal obstruction. To date, previous therapeutic strategies have been used to potentiate the recovery of renal function after RUUO; however, the mechanisms involving renal damage reduction are poorly described and sometimes focus on the recovery of renal functionality. Furthermore, using natural antioxidants has not been completely studied in the RUUO model. In this study, we selected sulforaphane (SFN) because it activates the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces an antioxidant response, decreasing oxidative stress and inflammation, preventing apoptosis. Thus, we pre-administrated SFN on the second day after UUO until day five, where we released the obstruction on the three days after UUO. Then, we assessed oxidative stress, inflammation, and apoptosis markers. Interestingly, we found that SFN administration in the RUUO model activated Nrf2, inducing its translocation to the nucleus to activate its target proteins. Thus, the Nrf2 activation upregulated glutathione (GSH) content and the antioxidant enzymes catalase, glutathione peroxidase (GPx), and glutathione reductase (GR), which reduced the oxidative stress markers. Moreover, the improvement of antioxidant response by SFN restored S-glutathionylation in the mitochondrial fraction. Activated Nrf2 also reduced inflammation by lessening the nucleotide-binding domain-like receptor family pyrin domain containing 3 and interleukin 1ß (IL-1ß) production. Reducing oxidative stress and inflammation prevented apoptosis by avoiding caspase 3 cleavage and increasing B-cell lymphoma 2 (Bcl2) levels. Taken together, the obtained results in our study showed that the upregulation of Nrf2 by SFN decreases oxidative stress, preventing inflammation and apoptosis cell death during the release of UUO.