INC Ignacio Chavez

Mexico City, Mexico

INC Ignacio Chavez

Mexico City, Mexico
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Snchez-Lozada L.-G.,INC Ignacio Chavez | Franco M.,INC Ignacio Chavez | Madero M.,INC Ignacio Chavez | Solak Y.,Selcuk University | And 3 more authors.
Nephrology Dialysis Transplantation | Year: 2011

Arteriolosclerosis (microvascular disease) may have a key role not only in driving salt-sensitive hypertension but also in mediating the development of chronic kidney disease, vascular dementia, stroke and coronary heart disease. In this paper, we review the evidence that these latter conditions result from the altered autoregulation that occurs when arterioles become diseased. We also discuss the increasing evidence that dietary intake of sugars rich in fructose may be driving the development of microvascular disease as a consequence of raising intracellular uric acid. We hypothesize that the treatment of microvascular disease may require a multifaceted approach by utilizing agents which aim at blocking of the reninangiotensin system, reducing oxidative stress, stimulating endothelial nitric oxide production and lowering uric acid levels. Paradoxically, agents that only stimulate nitric oxide, such as oestrogens, may increase the risk of poor outcomes if microvascular disease is not reversed. © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.2011Oxford University Press © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

PubMed | Karolinska Institutet, National Autonomous University of Nicaragua, León, Agencia para el Desarrollo y la Salud Agropecuaria, University of the Balearic Islands and 6 more.
Type: Journal Article | Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation | Year: 2015

Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.

PubMed | INC Ignacio Chavez., University of Colorado at Denver and University of Colorado
Type: | Journal: American journal of physiology. Renal physiology | Year: 2016

Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration.Recurrent exposure to heat with limited water availability was performed in male mice over a 5 week period, with one group receiving desmopressin twice daily and the other group received vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury was assessed.Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary NGAL), glomerular changes (mesangiolysis, matrix expansion) and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes and tubulointerstitial fibrosis in normal animals, and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity.Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy, and may be clinically relevant to the pathogenesis of Mesoamerican Nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2-receptor dependent pathway.

PubMed | University of Colorado at Denver, Boston University, INC Ignacio Chavez., Nagoya University and 3 more.
Type: | Journal: Journal of neurophysiology | Year: 2016

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.Wildtype and fructokinase-knockout mice were deprived of water for 24 hours. The supraoptic nucleus was evaluated for vasopressin and 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 fructose.Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wildtype mice was larger than that in fructokinase-knockout mice. Water-restricted wildtype 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 wildtype 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.

Lanaspa M.A.,University of Colorado at Denver | Sanchez-Lozada L.G.,University of Colorado at Denver | Sanchez-Lozada L.G.,INC Ignacio Chavez | Cicerchi C.,University of Colorado at Denver | And 13 more authors.
PLoS ONE | Year: 2012

Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. © 2012 Lanaspa et al.

Ishimoto T.,University of Colorado at Denver | Lanaspa M.A.,University of Colorado at Denver | Rivard C.J.,University of Colorado at Denver | Roncal-Jimenez C.A.,University of Colorado at Denver | And 19 more authors.
Hepatology | Year: 2013

Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 weeks. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. Conclusion: An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis. © 2013 by the American Association for the Study of Liver Diseases.

Madero M.,INC Ignacio Chavez | Perez-Pozo S.E.,Son Llatzer Hospital | Jalal D.,University of Colorado at Denver | Johnson R.J.,University of Colorado at Denver | Sanchez-Lozada L.G.,INC Ignacio Chavez
Current Hypertension Reports | Year: 2011

The association between fructose and increased blood pressure is still incompletely defined, because experimental studies have produced dissimilar conclusions. Amplified vasopressor responses to minimal stimuli and differing responses to fructose in peripheral versus central sites may explain the controversy. Fructose induces systemic hypertension through several mechanisms mainly associated with deleterious effects on target organs (kidney, endothelium, heart) exerted by the byproducts of its metabolism, such as uric acid. The kidney is particularly sensitive to the effects of fructose because high loads of this sugar reach renal tissue. In addition, fructose increases reabsorption of salt and water in the small intestine and kidney; thus the combination of salt and fructose has a synergistic effect in the development of hypertension. Clinical and epidemiologic studies have also linked fructose consumption with hypertension. Further studies are warranted in order to understand the role of fructose in the development of hypertension. © 2010 Springer Science+Business Media, LLC.

Roncal-Jimenez C.,University of Colorado at Denver | Lanaspa M.A.,University of Colorado at Denver | Jensen T.,University of Colorado at Denver | Sanchez-Lozada L.G.,INC Ignacio Chavez | Johnson R.J.,University of Colorado at Denver
Annals of Nutrition and Metabolism | Year: 2015

Dehydration, a condition that characterizes excessive loss of body water, is well known to be associated with acute renal dysfunction; however, it has largely been considered reversible and to be associated with no long-term effects on the kidney. Recently, an epidemic of chronic kidney disease has emerged in Central America in which the major risk factor seems to be recurrent heat-associated dehydration. This has led to studies investigating whether recurrent dehydration may lead to permanent kidney damage. Three major potential mechanisms have been identified, including the effects of vasopressin on the kidney, the activation of the aldose reductase-fructokinase pathway, and the effects of chronic hyperuricemia. The discovery of these pathways has also led to the recognition that mild dehydration may be a risk factor in progression of all types of chronic kidney diseases. Furthermore, there is some evidence that increasing hydration, particularly with water, may actually prevent CKD. Thus, a whole new area of investigation is developing that focuses on the role of water and osmolarity and their influence on kidney function and health. © 2015 S. Karger AG, Basel.

PubMed | National Autonomous University of Mexico, Hospital Universitario Of Maracaibo And Laboratory Of Immunobiology, INC Ignacio Chavez and University of Colorado at Denver
Type: | Journal: Oxidative medicine and cellular longevity | Year: 2015

We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750mg/kg BW), OA+Allopurinol (AP, 150mg/L drinking water), OA+Tempol (T, 15mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl--D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident.

PubMed | National Autonomous University of Mexico and INC Ignacio Chavez
Type: Journal Article | Journal: Free radical research | Year: 2016

Increased oxidative stress and inflammation have an important role in the pathophysiology of chronic kidney disease (CKD). On the other hand, more affordable therapeutic alternatives for treating this disease are urgently needed. Therefore, we compared the therapeutic efficacy of curcumin and mycophenolate mofetil (MMF) in 5/6 nephrectomy (5/6 Nx) model of CKD. Also, we evaluated whether both compounds provide benefit through the preservation of similar antioxidant mechanisms. Four groups of male Wistar were studied over a period of 4 wk. Control sham group (n=12), 5/6 Nx (n=12), 5/6 Nx+MMF (30mg/k BW/day, n=11) and 5/6 Nx+Curcumin (120mg/k BW/day, n=12). Renal function and markers of oxidative stress and inflammation were evaluated. Also Nrf2-Keap1 and renal dopamine, antioxidant pathways were assessed. 5/6 Nx induced an altered renal autoregulation response, proteinuria, and hypertension; these effects were in association with increased oxidative stress, endothelial dysfunction and renal inflammation. The mechanisms associated with these alterations included a reduced nuclear translocation of Nrf2 and hyperphosphorylation of dopamine D1 receptor with a concurrent overactivation of renal NADPH oxidase. Treatments with MMF and curcumin provided equivalent therapeutic efficacy as both prevented functional renal alterations as well as preserved antioxidant capacity and avoided renal inflammatory infiltration. Moreover, both treatments preserved Nrf2-Keap1 and renal dopamine antioxidant pathways. In summary, therapeutic strategies aimed to preserve renal antioxidant pathways can help to retard the progression of CKD.

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