Objective: Aquaporin-1 (AQP1) is expressed in the heart and it has been reported to transport nit... more Objective: Aquaporin-1 (AQP1) is expressed in the heart and it has been reported to transport nitric oxide (NO), an important regulator of cardiac function. Our aim was to study AQP1 abundance and localization, NO synthase (NOS) activity and AQP1 nitrosylation in response to osmotic stress induced by water restriction during postnatal growth. Design and method: Male Sprague-Dawley rats aged 25 and 50 days (n = 10) were divided in: R: water restriction 3 days; C: water ad libitum 3 days. NOS activity (14C-Arginine), AQP1 protein levels (Western Blot) and localization (immunohistochemistry) and AQP1 nitrosylation (colocalization of immunofluorescence signals of AQP1 and nitrosylated cysteine by confocal microscopy) were determined in cardiac tissue. We also evaluated the effects of NO donor sodium nitroprusside (SNP) on osmotic water permeability of cardiac membrane vesicles expressing AQP1 by stopped-flow spectrometry. Results: Water restriction induced a dehydration state in both age groups. Cardiac AQP1 was localized in the endocardium and endothelium in both age groups in control animals. Water restriction did not change AQP1 abundance or localization in the 25-day-old R group; however, in the 50-day-old group, AQP1 protein levels were increased and immunohistochemistry showed its localization on cardiomyocyte plasma membrane after water restriction. Cardiac NOS activity was increased in the youngest R group but it did not change in the 50-day-old R group. AQP1 nitrosylation was increased in R25 group, whereas there are no significant differences in colocalization of fluorescent signals between C or R animals aged 50 days. On the other hand, cardiac membrane vesicles expressing AQP1 presented a high water permeability coefficient (Pf: 326+/-17 &mgr;m/s, n = 6) indicated water transport by aquaporins and pretreatment with SNP decreased water permeability (Pf: 102+/-4 &mgr;m/s, n = 5). Conclusions: Cardiac NO system and AQP1 abundance and localization during osmotic stress in vivo depend on postnatal age. Increased activity of cardiac NO system in the youngest group may induce AQP1 nitrosylation, decreasing osmotic water permeability of cardiac membranes and having a negative impact on cardiac water balance. In the 50-day-old group, changes in AQP1 abundance and localization may contribute to maintaining cardiac water homeostasis during hypovolemic state.
Enterohemorrhagic Escherichia coli (EHEC) infections can result in a wide range of clinical prese... more Enterohemorrhagic Escherichia coli (EHEC) infections can result in a wide range of clinical presentations despite that EHEC strains belong to the O157:H7 serotype, one of the most pathogenic forms. Although pathogen virulence influences disease outcome, we emphasize the concept of host-pathogen interactions, which involve resistance or tolerance mechanisms in the host that determine total host fitness and bacterial virulence.
Hemolytic Uremic Syndrome (HUS), a disease triggered by Shiga toxin (Stx), is characterized by he... more Hemolytic Uremic Syndrome (HUS), a disease triggered by Shiga toxin (Stx), is characterized by hemolytic anemia, thrombocytopenia and renal failure. The inflammatory response mediated by polymorphonuclear neutrophils (PMNs) and monocytes is essential to HUS onset. Still, the role of anti-inflammatory cytokines is less clear. The deficiency of IL-10, an anti-inflammatory cytokine, leads to severe pathology in bacterial infections but also to beneficial effects in models of sterile injury. The aim of this work was to analyze the role of IL-10 during HUS. Control and IL-10 lacking mice (IL-10−/−) were intravenously injected with Stx type 2 (Stx2) and survival rate was evaluated. PMN and circulating and renal pro- and anti-inflammatory factors were analyzed by FACS and enzyme-linked immunosorbent assay (ELISA) respectively. IL-10−/− mice showed a higher survival associated with lower renal damage reflected by reduced plasma urea and creatinine levels than control mice. Circulating PMN i...
IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patter... more IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patterns of clinical presentation, and lacks specific treatment. In general, it slowly progresses to end-stage renal disease. The clinical course and the response to therapy are usually assessed with proteinuria and serum creatinine. Validated biomarkers have not been identified yet. In this report, we present a case of acute renal injury with proteinuria and microscopic hematuria in a young male. A kidney biopsy disclosed IgA nephropathy. Podocyturia was significantly elevated compared to normal subjects. Proteinuria, renal function, and podocyturia improved promptly after steroids and these variables remained normal after one year of follow-up, when steroids had already been discontinued and patient continued on valsartan and amiloride. Our report demonstrates that podocyturia is critically elevated during an acute episode of IgA nephropathy, and its occurrence may explain the grim long-term...
Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia i... more Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia is an irreversible event that antedates proteinuria and leads to chronic renal failure. We evaluated a potential mechanism of podocyte detachment via the expression of the urokinase-type Plasminogen Activator Receptor (uPAR) in urinary podocytes of Fabry patients.Methods. This is a cross-sectional study that included controls (n=20) and Fabry patients (n=44) either untreated (n=23) or treated with agalsidase-β(n=21).Variables. Variables are estimated glomerular filtration rate (eGFR), urinary protein : creatinine ratio, and urinary uPAR+ podocyte : creatinine ratio. uPAR mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes.Results. Controls and Fabry patients had similar age, gender, and renal function. Urinary uPAR+ podocytes were higher in patients than in controls. Untreated patients were significantly you...
Background. There is a gender disparity in the incidence, prevalence, and progression of renal di... more Background. There is a gender disparity in the incidence, prevalence, and progression of renal disease. The object of this paper is to evaluate the presence and type of renal lesion in normogonadic and hypogonadic male rats in a mild hyperuricemia induced condition and exposed to a high-fructose diet. Methods. 56 adult male Wistar rats were used. Animals were divided into two groups, one normogonadic (NGN) and one hypogonadic (HGN), and each group was divided into four subgroups in accordance with the treatment: control with only water (C), fructose (F), oxonic acid (OA), and fructose + oxonic acid (FOA). Renal changes were evaluated by measuring glomerulosclerosis, fibrosis, and arteriolar media/lumen (M/L) ratio.Results. The OA and FOA groups presented significantly hypertension (p<0.001). The OA group significantly increased (p<0.05) the percentage of glomerulosclerosis as well as the FOA group (p<0.001). When comparing NGN versus HGN, we observed a trend to a lower glom...
No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease cau... more No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease caused by mutations in collagen type IV, a crucial component of the glomerular basement membrane. Kidney failure is usually a major complication of the disease, and patients require renal replacement therapy early in life. Microhematuria and subsequently proteinuria are hallmarks of kidney involvement, which are due to primary basement membrane alterations that mainly cause endothelial thrombosis and podocyte contraction and ulterior irreversible detachment. Commonly drug-based approaches include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are employed to reduce proteinuria and thus retard kidney disease progression and cardiovascular morbidity and mortality. However, as any hereditary disease, it is expressed as early as in the intrauterine life, and usually an index case is helpful to detect family-related cases. As no specific treatment exists, patho...
The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matte... more The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matter of debate, particularly when no overt classical clinical signs or symptoms are present. With respect to Fabry nephropathy, a dual problem coexists: the reluctance of many nephrologists to start enzyme replacement infusion until signs of renal disease appear as the appearance of proteinuria or an elevation in serum creatinine and the lack of validated biomarkers of early renal damage. In this regard, proteinuria is nowadays considered as an early and appropriate marker of kidney disease and of cardiovascular morbidity and mortality. However, in this report we demonstrate that podocyturia antedates the classical appearance of proteinuria and could be considered as an even earlier biomarker of kidney damage. Podocyturia may be a novel indication for the initiation of therapy in Fabry disease.
INTRODUCCION In nephrotic syndrome, increased podocyturia accompanies pathologic proteinuria. The... more INTRODUCCION In nephrotic syndrome, increased podocyturia accompanies pathologic proteinuria. The therapeutic regimen with enalapril, losartan and amiloride could reduce both variables. OBJETIVES Evaluate the anti-proteinuric effect of 2 non-immunological therapeutic regimens, the quantitative relationship between podocyturia and proteinuria. MATERIAL AND METHODS We included children aged 4 to 12 years with corticoresistant nephrotic syndrome, using 2 different schemes: group A, enalapril+losartan, and group B, enalapril+losartan+amiloride. RESULTS In group A, 17 patients completed the study, the initial mean proteinuria was 39mg/m2/h and mean proteinuria at the end was 24mg/m2/h, while in group B 14 patients were treated and the initial average proteinuria was 36mg/m2/h and the end average proteinuria was 13mg/m2/h. The paired T test showed significant differences in the decrease in proteinuria, for patients in group B without variation in podocyturia. The 2 factors associated with an increase in proteinuria were podocyturia and the time elapsed from the diagnosis of cortico-resistant nephrotic syndrome to the start of treatment anti-proteinuric. CONCLUSIONS The use of amiloride decreased proteinuria, without significantly modifying podocyturia; we did not observe a positive relationship between both variables.
Objective: Aquaporin-1 (AQP1) is expressed in the heart and it has been reported to transport nit... more Objective: Aquaporin-1 (AQP1) is expressed in the heart and it has been reported to transport nitric oxide (NO), an important regulator of cardiac function. Our aim was to study AQP1 abundance and localization, NO synthase (NOS) activity and AQP1 nitrosylation in response to osmotic stress induced by water restriction during postnatal growth. Design and method: Male Sprague-Dawley rats aged 25 and 50 days (n = 10) were divided in: R: water restriction 3 days; C: water ad libitum 3 days. NOS activity (14C-Arginine), AQP1 protein levels (Western Blot) and localization (immunohistochemistry) and AQP1 nitrosylation (colocalization of immunofluorescence signals of AQP1 and nitrosylated cysteine by confocal microscopy) were determined in cardiac tissue. We also evaluated the effects of NO donor sodium nitroprusside (SNP) on osmotic water permeability of cardiac membrane vesicles expressing AQP1 by stopped-flow spectrometry. Results: Water restriction induced a dehydration state in both age groups. Cardiac AQP1 was localized in the endocardium and endothelium in both age groups in control animals. Water restriction did not change AQP1 abundance or localization in the 25-day-old R group; however, in the 50-day-old group, AQP1 protein levels were increased and immunohistochemistry showed its localization on cardiomyocyte plasma membrane after water restriction. Cardiac NOS activity was increased in the youngest R group but it did not change in the 50-day-old R group. AQP1 nitrosylation was increased in R25 group, whereas there are no significant differences in colocalization of fluorescent signals between C or R animals aged 50 days. On the other hand, cardiac membrane vesicles expressing AQP1 presented a high water permeability coefficient (Pf: 326+/-17 &mgr;m/s, n = 6) indicated water transport by aquaporins and pretreatment with SNP decreased water permeability (Pf: 102+/-4 &mgr;m/s, n = 5). Conclusions: Cardiac NO system and AQP1 abundance and localization during osmotic stress in vivo depend on postnatal age. Increased activity of cardiac NO system in the youngest group may induce AQP1 nitrosylation, decreasing osmotic water permeability of cardiac membranes and having a negative impact on cardiac water balance. In the 50-day-old group, changes in AQP1 abundance and localization may contribute to maintaining cardiac water homeostasis during hypovolemic state.
Enterohemorrhagic Escherichia coli (EHEC) infections can result in a wide range of clinical prese... more Enterohemorrhagic Escherichia coli (EHEC) infections can result in a wide range of clinical presentations despite that EHEC strains belong to the O157:H7 serotype, one of the most pathogenic forms. Although pathogen virulence influences disease outcome, we emphasize the concept of host-pathogen interactions, which involve resistance or tolerance mechanisms in the host that determine total host fitness and bacterial virulence.
Hemolytic Uremic Syndrome (HUS), a disease triggered by Shiga toxin (Stx), is characterized by he... more Hemolytic Uremic Syndrome (HUS), a disease triggered by Shiga toxin (Stx), is characterized by hemolytic anemia, thrombocytopenia and renal failure. The inflammatory response mediated by polymorphonuclear neutrophils (PMNs) and monocytes is essential to HUS onset. Still, the role of anti-inflammatory cytokines is less clear. The deficiency of IL-10, an anti-inflammatory cytokine, leads to severe pathology in bacterial infections but also to beneficial effects in models of sterile injury. The aim of this work was to analyze the role of IL-10 during HUS. Control and IL-10 lacking mice (IL-10−/−) were intravenously injected with Stx type 2 (Stx2) and survival rate was evaluated. PMN and circulating and renal pro- and anti-inflammatory factors were analyzed by FACS and enzyme-linked immunosorbent assay (ELISA) respectively. IL-10−/− mice showed a higher survival associated with lower renal damage reflected by reduced plasma urea and creatinine levels than control mice. Circulating PMN i...
IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patter... more IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patterns of clinical presentation, and lacks specific treatment. In general, it slowly progresses to end-stage renal disease. The clinical course and the response to therapy are usually assessed with proteinuria and serum creatinine. Validated biomarkers have not been identified yet. In this report, we present a case of acute renal injury with proteinuria and microscopic hematuria in a young male. A kidney biopsy disclosed IgA nephropathy. Podocyturia was significantly elevated compared to normal subjects. Proteinuria, renal function, and podocyturia improved promptly after steroids and these variables remained normal after one year of follow-up, when steroids had already been discontinued and patient continued on valsartan and amiloride. Our report demonstrates that podocyturia is critically elevated during an acute episode of IgA nephropathy, and its occurrence may explain the grim long-term...
Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia i... more Background. Despite enzyme replacement therapy, Fabry nephropathy still progresses. Podocyturia is an irreversible event that antedates proteinuria and leads to chronic renal failure. We evaluated a potential mechanism of podocyte detachment via the expression of the urokinase-type Plasminogen Activator Receptor (uPAR) in urinary podocytes of Fabry patients.Methods. This is a cross-sectional study that included controls (n=20) and Fabry patients (n=44) either untreated (n=23) or treated with agalsidase-β(n=21).Variables. Variables are estimated glomerular filtration rate (eGFR), urinary protein : creatinine ratio, and urinary uPAR+ podocyte : creatinine ratio. uPAR mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes.Results. Controls and Fabry patients had similar age, gender, and renal function. Urinary uPAR+ podocytes were higher in patients than in controls. Untreated patients were significantly you...
Background. There is a gender disparity in the incidence, prevalence, and progression of renal di... more Background. There is a gender disparity in the incidence, prevalence, and progression of renal disease. The object of this paper is to evaluate the presence and type of renal lesion in normogonadic and hypogonadic male rats in a mild hyperuricemia induced condition and exposed to a high-fructose diet. Methods. 56 adult male Wistar rats were used. Animals were divided into two groups, one normogonadic (NGN) and one hypogonadic (HGN), and each group was divided into four subgroups in accordance with the treatment: control with only water (C), fructose (F), oxonic acid (OA), and fructose + oxonic acid (FOA). Renal changes were evaluated by measuring glomerulosclerosis, fibrosis, and arteriolar media/lumen (M/L) ratio.Results. The OA and FOA groups presented significantly hypertension (p<0.001). The OA group significantly increased (p<0.05) the percentage of glomerulosclerosis as well as the FOA group (p<0.001). When comparing NGN versus HGN, we observed a trend to a lower glom...
No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease cau... more No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease caused by mutations in collagen type IV, a crucial component of the glomerular basement membrane. Kidney failure is usually a major complication of the disease, and patients require renal replacement therapy early in life. Microhematuria and subsequently proteinuria are hallmarks of kidney involvement, which are due to primary basement membrane alterations that mainly cause endothelial thrombosis and podocyte contraction and ulterior irreversible detachment. Commonly drug-based approaches include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are employed to reduce proteinuria and thus retard kidney disease progression and cardiovascular morbidity and mortality. However, as any hereditary disease, it is expressed as early as in the intrauterine life, and usually an index case is helpful to detect family-related cases. As no specific treatment exists, patho...
The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matte... more The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matter of debate, particularly when no overt classical clinical signs or symptoms are present. With respect to Fabry nephropathy, a dual problem coexists: the reluctance of many nephrologists to start enzyme replacement infusion until signs of renal disease appear as the appearance of proteinuria or an elevation in serum creatinine and the lack of validated biomarkers of early renal damage. In this regard, proteinuria is nowadays considered as an early and appropriate marker of kidney disease and of cardiovascular morbidity and mortality. However, in this report we demonstrate that podocyturia antedates the classical appearance of proteinuria and could be considered as an even earlier biomarker of kidney damage. Podocyturia may be a novel indication for the initiation of therapy in Fabry disease.
INTRODUCCION In nephrotic syndrome, increased podocyturia accompanies pathologic proteinuria. The... more INTRODUCCION In nephrotic syndrome, increased podocyturia accompanies pathologic proteinuria. The therapeutic regimen with enalapril, losartan and amiloride could reduce both variables. OBJETIVES Evaluate the anti-proteinuric effect of 2 non-immunological therapeutic regimens, the quantitative relationship between podocyturia and proteinuria. MATERIAL AND METHODS We included children aged 4 to 12 years with corticoresistant nephrotic syndrome, using 2 different schemes: group A, enalapril+losartan, and group B, enalapril+losartan+amiloride. RESULTS In group A, 17 patients completed the study, the initial mean proteinuria was 39mg/m2/h and mean proteinuria at the end was 24mg/m2/h, while in group B 14 patients were treated and the initial average proteinuria was 36mg/m2/h and the end average proteinuria was 13mg/m2/h. The paired T test showed significant differences in the decrease in proteinuria, for patients in group B without variation in podocyturia. The 2 factors associated with an increase in proteinuria were podocyturia and the time elapsed from the diagnosis of cortico-resistant nephrotic syndrome to the start of treatment anti-proteinuric. CONCLUSIONS The use of amiloride decreased proteinuria, without significantly modifying podocyturia; we did not observe a positive relationship between both variables.
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