RESUMEN

Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are the main causes of nephrotic syndrome in the world. The complement system appears to play an important role in the pathogenesis of these diseases. To evaluate the deposition of immunoglobulins and particles of the complement system in renal biopsies of patients with FSGS and MCD and relate to laboratory data, we selected 59 renal biopsies from patients with podocytopathies, 31 from patients with FSGS and 28 with MCD. Epidemiological, clinical, laboratory information and the prognosis of these patients were evaluated. Analysis of the deposition of IgM, IgG, C3, C1q and C4d in renal biopsies was performed. We related IgM and C3 deposition with laboratory parameters. Statistical analysis was performed using GraphPad Prism version 7.0. Glomerular deposition of IgM was significantly higher in the FSGS group, as was codeposition of IgM and C3. The clinical course of patients and laboratory data were also worse in cases of FSGS, with a higher percentage progressing to chronic kidney disease and death. Patients with C3 deposition had significantly higher mean serum creatinine and significantly lower eGFR, regardless of disease. Patients with FSGS had more IgM and C3 deposition in renal biopsies, worse laboratory data and prognosis than patients with MCD. C3 deposition, both in FSGS and MCD, appears to be related to worsening renal function.

Asunto(s)

Complemento C3 , Glomeruloesclerosis Focal y Segmentaria , Inmunoglobulina M , Glomérulos Renales , Nefrosis Lipoidea , Humanos , Inmunoglobulina M/metabolismo , Complemento C3/metabolismo , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/inmunología , Femenino , Masculino , Adulto , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Persona de Mediana Edad , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/metabolismo , Podocitos/patología , Podocitos/metabolismo , Adulto Joven , Adolescente , Pronóstico , Biopsia , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Síndrome Nefrótico/inmunología , Anciano

RESUMEN

Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and thus to changes in the polarity (M1/M2) of macrophages. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerulosclerosis and decreased macrophage-myofibroblast transition in DN rats. Therefore, we aimed to investigate the effect of MRS1754 on the glomerular expression/secretion of chemoattractants, the intraglomerular infiltration of leukocytes, and macrophage polarity in DN rats. Kidneys/glomeruli of non-diabetic, DN, and MRS1754-treated DN rats were processed for transcriptomic analysis, immunohistopathology, ELISA, and in vitro macrophage migration assays. The transcriptomic analysis identified an upregulation of transcripts and pathways related to the immune system in the glomeruli of DN rats, which was attenuated using MRS1754. The antagonism of the A2BAR decreased glomerular expression/secretion of chemoattractants (CCL2, CCL3, CCL6, and CCL21), the infiltration of macrophages, and their polarization to M2 in DN rats. The in vitro macrophages migration induced by conditioned-medium of DN glomeruli was significantly decreased using neutralizing antibodies against CCL2, CCL3, and CCL21. We concluded that the pharmacological blockade of the A2BAR decreases the transcriptional expression of genes/pathways related to the immune response, protein expression/secretion of chemoattractants, as well as the infiltration of macrophages and their polarization toward the M2 phenotype in the glomeruli of DN rats, suggesting a new mechanism implicated in the antifibrotic effect of MRS1754.

Asunto(s)

Acetamidas , Antagonistas del Receptor de Adenosina A2 , Polaridad Celular , Factores Quimiotácticos , Nefropatías Diabéticas , Glomérulos Renales , Macrófagos , Purinas , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/inmunología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Factores Quimiotácticos/antagonistas & inhibidores , Factores Quimiotácticos/genética , Factores Quimiotácticos/metabolismo , Polaridad Celular/efectos de los fármacos , Polaridad Celular/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Antagonistas del Receptor de Adenosina A2/farmacología , Receptor de Adenosina A2B , Acetamidas/farmacología , Purinas/farmacología , Animales , Ratas , Movimiento Celular/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Transcripción Genética/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , Inmunidad/efectos de los fármacos , Inmunidad/genética

RESUMEN

BACKGROUND: Acute post-streptococcal glomerulonephritis (APSGN) is an immune- complex (ICs) mediated glomerular disease triggered by group A ß-hemolytic streptococcus (GAS) or Streptococcus pyogenes infections. APSGN represents a major cause of acquired kidney injury in children. METHODS: This non-systematic review summarizes recent evidence on APSGN. We discuss the epidemiology, pathogenesis, clinical and laboratory findings, histopathology, treatment and prognosis of the disease. RESULTS: The median APSGN incidence in children in developing countries is estimated at 24.3/100,000 per year, compared with 6.2/100,000 per year in developed countries. Nephritis-associated plasmin receptor, identified as glyceraldehyde-3-phosphate dehydrogenase, and the cationic cysteine proteinase streptococcal pyrogenic exotoxin B are thought to be two leading streptococcal antigens involved in the pathogenesis of APSGN, which activate the complement system, mainly via the alternative but also the lectin pathway. This process is critical for the generation of inflammation by the ICs deposited in the glomerulus. The classic phenotype is an acute diffuse proliferative glomerulonephritis leading to features of the nephritic syndrome, including hematuria, oliguria, hypertension and edema. The histopathology shows that the glomeruli are diffusely affected, mostly presenting enlarged glomerular tuffs due to hypercellularity. Proliferative endothelial and mesangial cells and inflammation have also been observed. APSGN frequently has spontaneous recovery. There is no specific therapy, but its morbidity and mortality are drastically reduced by the prevention and/or treatment of complications. CONCLUSION: Despite recent advances, the pathogenesis of APSGN is not fully understood. There is no specific treatment for APSGN. The prognosis is generally good. However, some cases may evolve into chronic kidney disease.

Asunto(s)

Glomerulonefritis , Infecciones Estreptocócicas , Enfermedad Aguda , Antígenos Bacterianos , Glomerulonefritis/etiología , Glomerulonefritis/patología , Humanos , Inflamación/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/tratamiento farmacológico

RESUMEN

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor ß (TGFß), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1+ cells. The interleukin-1ß (IL-1ß) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.

Asunto(s)

Lesión Renal Aguda/tratamiento farmacológico , Aspirina/farmacología , Ácidos Docosahexaenoicos/farmacología , Glomérulos Renales/efectos de los fármacos , Sepsis/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Albúminas/farmacología , Animales , Biomarcadores/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Pruebas de Función Renal/métodos , Glomérulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Proteinuria/inducido químicamente , Proteinuria/tratamiento farmacológico , Proteinuria/metabolismo , ARN Mensajero/metabolismo , Sepsis/metabolismo

RESUMEN

Chronic kidney disease (CKD) is a major public health concern and its prevalence and incidence are rising quickly. It is a non-communicable disease primarily caused by diabetes and/or hypertension and is associated with high morbidity and mortality. Despite decades of research efforts, the pathogenesis of CKD remains a puzzle with missing pieces. Understanding the cellular and molecular mechanisms that govern the loss of kidney function is crucial. Abrupt regulation of gene expression in kidney cells is apparent in CKD and shown to be responsible for disease onset and progression. Gene expression regulation extends beyond DNA sequence and involves epigenetic mechanisms including changes in DNA methylation and post-translational modifications of histones, driven by the activity of specific enzymes. Recent advances demonstrate the essential participation of epigenetics in kidney (patho)physiology, as its actions regulate both the integrity of cells but also triggers deleterious signaling pathways. Here, we review the known epigenetic processes regulating the complex filtration unit of the kidney, the glomeruli. The review will elaborate on novel insights into how epigenetics contributes to cell injury in the CKD setting majorly focusing on kidney glomerular cells: the glomerular endothelial cells, the mesangial cells, and the specialized and terminally differentiated podocyte cells.

Asunto(s)

Susceptibilidad a Enfermedades , Epigénesis Genética , Regulación de la Expresión Génica , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Glomérulos Renales/citología , Glomérulos Renales/metabolismo , Animales , Biomarcadores , Metilación de ADN , Células Endoteliales/metabolismo , Histonas/metabolismo , Humanos , Enfermedades Renales/patología , Glomérulos Renales/patología , Células Mesangiales/metabolismo , Podocitos/metabolismo , Procesamiento Proteico-Postraduccional

RESUMEN

Advanced glycation end products (AGEs) play an important role in oxidative stress and inflammation, processes implicated in the development and progression of kidney dysfunction. In the present study, we investigated the participation of the pro-oxidant protein thioredoxin-interacting protein (TXNIP) and of epigenetic mechanisms on kidney tissue (in vivo, in non-diabetic rats) and on terminally differentiated glomerular podocytes (in vitro) chronically exposed to AGEs. AGEs induced total kidney and glomerular TXNIP expression and decreased H3K27me3 content. Concomitant treatment with the antioxidant N-acetyl-cysteine (NAC) reversed only the increased TXNIP expression. TXNIP expression positively correlated with proteinuria and negatively correlated with H3K27me3 content. In vitro studies in podocytes showed that 72 h exposure to AGEs decreased nephrin expression and increased Txnip, Nox4, Col4a1, and epithelial-to-mesenchymal transition (EMT) markers (Acta2, Snail1, and Tgfb1). Podocytes treatment with NAC reversed Nox4, Col4a1, Acta2, and Tgfb1 increased expression but did not abrogate the reduced expression of nephrin. MiR-29a expression was downregulated by AGEs in vivo, but not in vitro. In conclusion, treatment of non-diabetic rats with AGEs induced TXNIP expression and decreased the contents of the repressive epigenetic mark H3K27me3 and of miR-29a, potentially driving injury to glomerular filtration barrier and podocytes dysfunction.

Asunto(s)

Proteínas de Ciclo Celular/genética , Nefropatías Diabéticas/metabolismo , Productos Finales de Glicación Avanzada/farmacología , Animales , Antioxidantes/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/genética , Epigénesis Genética/genética , Células Epiteliales/metabolismo , Expresión Génica/genética , Regulación de la Expresión Génica/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Histonas , Riñón/citología , Riñón/metabolismo , Glomérulos Renales/metabolismo , Masculino , Proteínas de la Membrana , Estrés Oxidativo , Podocitos/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

BACKGROUND: Renal fibrosis is the result of the interaction of cellular and molecular pathways, which is induced by sustained glomerular injury and involves the podocytes and multiple profibrotic factors. In this study, we investigated the correlation of the mRNA expression of podocyte proteins and profibrotic factors with renal fibrosis measured in renal biopsies of patients with primary and secondary glomerulopathies. METHODS: Eighty-four adult patients with primary or secondary glomerular diseases and 12 controls were included. Demographic and clinical data were collected. Seventy-two percent of the renal biopsies were done less than one year from clinical disease manifestation. The quantification of the podocyte-associated mRNAs of alpha-actinin-4, podocin, and podocalyxin, as well as of the profibrotic factors TGF-ß1, CTGF, and VEGF-A were quantified by real-time polymerase chain reaction. The percent positive area of renal fibrosis was measured by immunohistochemistry staining, using anti-CTGF and anti-HHF35 antibodies and unpolarized Sirius Red. Correlations between the expression of tissue mRNAs and the positive area of fibrosis for the measured markers were made by Spearman's rank correlation coefficient. RESULTS: In relation to control biopsies, podocyte-specific proteins were downregulated in podocytopathies, in proliferative nephritis, in diabetic kidney disease (DRD), and in IgA nephropathy (IgAN). Messenger RNA of TGF-ß1, CTGF, and VEGF-A was upregulated in patients with podocytopathies and in DRD but not in proliferative nephritis and IgAN. Tissue mRNA expression of TGF-ß1, CTGF, and VEGF-A were strongly correlated with renal fibrosis, as measured by HHF35; however, the correlation, albeit significant, was moderate for Sirius Red and weak for CTGF. The percent positive area of renal fibrosis measured by Sirius Red was similar between podocytopathies and DRD and significantly higher in podocytopathies compared to IgAN or proliferative nephritis. CONCLUSIONS: In patients with glomerular diseases, the mRNA of TGF-ß1, CTGF, and VEGF-A correlated positively with the extent of renal fibrosis, and the positive area of fibrosis was larger in the podocytopathies and in DRD as measured by Sirius Red. The pathways connecting podocyte damage and activation of profibrotic factors to kidney tissue fibrosis need to be better investigated.

Asunto(s)

Glomérulos Renales/patología , Podocitos/patología , Adulto , Biomarcadores/metabolismo , Biopsia , Factor de Crecimiento del Tejido Conjuntivo/genética , Femenino , Humanos , Glomérulos Renales/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Factor de Crecimiento Transformador beta1/genética , Factor A de Crecimiento Endotelial Vascular/genética

RESUMEN

There are controversies whether Minimal Change Disease (MCD) and Focal and Segmental Glomerulosclerosis (FSGS) are distinct glomerular lesions or different manifestations within the same spectrum of diseases. The uPAR (urokinase-type plasminogen activator receptor) and some slit diaphragm proteins may be altered in FSGS glomeruli and may function as biomarkers of the disease in renal biopsies. Thus, this study aims to evaluate the diagnostic potential of uPAR and glomerular proteins for differentiation between MCD and FSGS in renal pediatric biopsy. Renal biopsies from 50 children between 2 and 18 years old were selected, with diagnosis of MCD (n = 29) and FSGS (n = 21). Control group consisted of pediatric autopsies (n = 15) from patients younger than 18 years old, with no evidences of renal dysfunction. In situ expressions of WT1, nephrin, podocin and uPAR were evaluated by immunoperoxidase technique. Renal biopsy of patients with MCD and FSGS expressed fewer WT1 (p≤0.0001, F = 19.35) and nephrin (p<0.0001; H = 21.54) than patients in the control group. FSGS patients expressed fewer podocin than control (p<0.0359, H = 6.655). FSGS cases expressed more uPAR than each of control and MCD (p = 0.0019; H = 12.57) and there was a positive and significant correlation between nephrin and podocin (p = 0.0026, rS = 0.6502) in these cases. Podocin had sensitivity of 73.3% and specificity of 86.7% (p = 0.0068) and uPAR had sensitivity of 78.9% and specificity of 73.3% (p = 0.0040) for diagnosis of FSGS patients. The main limitation of the study is the limited number of cases due to the difficulty in performing biopsy in pediatric patients. Podocin and uPAR are good markers for FSGS and differentiate these cases from MCD, reinforcing the theory of distinct glomerular diseases. These findings suggest that podocin and uPAR can be used as biomarkers in the routine analysis of renal biopsies in cases of podocytopathies when the lesion (sclerosis) is not sampled.

Asunto(s)

Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Péptidos y Proteínas de Señalización Intracelular/genética , Glomérulos Renales/metabolismo , Proteínas de la Membrana/genética , Nefrosis Lipoidea/diagnóstico , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Adolescente , Autopsia , Biomarcadores/metabolismo , Biopsia , Estudios de Casos y Controles , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Expresión Génica , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Glomérulos Renales/patología , Masculino , Proteínas de la Membrana/metabolismo , Nefrosis Lipoidea/genética , Nefrosis Lipoidea/metabolismo , Nefrosis Lipoidea/patología , Valor Predictivo de las Pruebas , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Proteínas WT1/genética , Proteínas WT1/metabolismo

RESUMEN

Long-term lithium treatment was associated with chronic kidney disease and renal failure although the underlying pathogenic mechanisms are not certainty known. The aim of this study was to evaluate changes in oxidative stress measures as well as renal functional and structural alterations associated with chronic use of lithium in rats. Forty Wistar male rats were randomized into four groups: control groups fed ad libitum powered standard diet for 1 and 3 months and experimental groups fed ad libitum the same diet supplemented with 60 mmol/kg diet for 1 and 3 months. Histopathological changes, laboratory parameters, and oxidative stress measurements were assessed at months 1 and 3. The experimental animals showed alteration of the cortical tubules from the first month of lithium-treatment and a decrease in the glomerular filtration rate and in the glomerular area at the third month. There was an increase in thiobarbituric acid reactive substances and carbonyls, as well as an increase in reduced glutathione, in the kidney of rats exposed to lithium. These changes were evident from the first month of treatment and remained throughout the experiment. Our results suggest that, oxidative stress could be one of the pathogenic mechanisms involved in the structural and functional alterations of the kidney associated with prolonged use of lithium. The study of the pathogenic mechanisms involved in lithium-induced nephropathy is a critical issue for the development of new strategies for prevention and/or early detection.

Asunto(s)

Enfermedades Renales/sangre , Enfermedades Renales/inducido químicamente , Litio/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Tasa de Filtración Glomerular/efectos de los fármacos , Glutatión/metabolismo , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Masculino , Ratas , Ratas Wistar , Insuficiencia Renal/sangre , Insuficiencia Renal/inducido químicamente , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

There is a strong correlation between inadequate gestational and postpartum nutrition and the occurrence of cardiovascular diseases. The present study investigated the effects of a maternal low-protein diet and neonatal overfeeding on the oxidative balance and morphology of the renal cortex of male Wistar rats. Two independent protocols were used. First, pregnant Wistar rats received diets containing either 17% (normal protein) or 8% (low protein) casein throughout pregnancy and lactation. Second, the litter size was reduced by one-third on the third postnatal day to induce overnourishment in offspring. At 30 days, the oxidative balance and morphology of the renal cortex were analyzed. There was a small but significant increase in renal corpuscle area in the low protein (LP, 5%) and overnutrition (ON, 8%) groups. Glomerular tuft area also increased in LP (6%) and ON (9%), as did glomerular cellularity (LP, +11%; ON, +12%). In the oxidative stress analyses, both nutritional insults significantly elevated lipid peroxidation (LP, +18%; ON, +135%) and protein oxidation (LP, +40%; ON, +65%) while significantly reducing nonenzymatic antioxidant defenses, measured as reduced glutathione (LP, -32%; ON, -45%) and total thiol content (LP, -28%; ON, -24%). We also observed a decrease in superoxide dismutase (LP, -78%; ON, -51%), catalase (LP, -18%; ON, -61%), and glutathione S-transferase (only in ON, -44%) activities. Our results demonstrate that nutritional insults, even those of a very different nature, during perinatal development can result in similar changes in oxidative parameters and glomerular morphology in the renal cortex.

Asunto(s)

Dieta con Restricción de Proteínas/efectos adversos , Corteza Renal/metabolismo , Glomérulos Renales/patología , Hipernutrición/metabolismo , Hipernutrición/patología , Estrés Oxidativo , Animales , Animales Recién Nacidos , Antioxidantes/metabolismo , Peso Corporal , Femenino , Corteza Renal/patología , Glomérulos Renales/metabolismo , Peroxidación de Lípido , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar

RESUMEN

BACKGROUND: Activated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF-1α (stromal cell-derived factor 1α; endogenous CXCR4 [C-X-C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF-1α/CXCR4 axis activates CFs, PGVSMCs, or GMCs. METHODS AND RESULTS: Here we investigated whether SDF-1α activates CFs, PGVSMCs, and GMCs to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF-1α and previous experiments show that growth-promoting peptides have greater effects in cells from genetically-hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin (DPP4 inhibitor) and in cells from normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar-Kyoto rat CFs, PGVSMCs, and GMCs express CXCR4 receptors and DPP4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF-1α causes concentration-dependent increases in the proliferation (cell number) and hypertrophy (3H-leucine incorporation) of and collagen production (3H-proline incorporation) by CFs, PGVSMCs, and GMCs; (3) that sitagliptin augments these effects of SDF-1α; (4) that interactions between SDF-1α and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR4 antagonism (AMD3100) blocks all effects of SDF-1α; and (6) that SDF-1α/CXCR4 signal transduction likely involves the RACK1 (receptor for activated C kinase 1)/Gßγ/PLC (phospholipase C)/PKC (protein kinase C) signaling complex. CONCLUSIONS: The SDF-1α/CXCR4 axis drives proliferation and hypertrophy of and collagen production by CFs, PGVSMCs, and GMCs, particularly in cells from genetically hypertensive animals and when DPP4 is inhibited.

Asunto(s)

Cardiomiopatía Hipertrófica/genética , Quimiocina CXCL12/genética , Colágeno/biosíntesis , Regulación de la Expresión Génica , Células Mesangiales/patología , Músculo Liso Vascular/patología , Miocardio/patología , Animales , Western Blotting , Cardiomiopatía Hipertrófica/metabolismo , Cardiomiopatía Hipertrófica/patología , Proliferación Celular , Células Cultivadas , Quimiocina CXCL12/biosíntesis , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fibroblastos/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Células Mesangiales/metabolismo , Microvasos/metabolismo , Microvasos/patología , Músculo Liso Vascular/metabolismo , Miocardio/metabolismo , ARN/genética , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR4/biosíntesis , Receptores CXCR4/genética , Arteria Renal/metabolismo , Arteria Renal/patología

RESUMEN

Chronic kidney disease (CKD) is considered a public health problem, assuming epidemic proportions worldwide. In this context, the preponderance of CKD prevalence in male over age-matched female patients is of note. In the present study, we investigated the impact of the gender on the development of experimental CKD induced by chronic nitric oxide (NO) inhibition in Wistar male and female rats through the administration of L-NAME. CKD model induced by L-NAME is characterized by systemic vasoconstriction, resulting in severe hypertension, albuminuria, renal ischemia, glomerulosclerosis, interstitial expansion, and macrophage infiltration. After 30 days of CKD induction, male NAME rats exhibited remarkable albuminuria, augmented cortical histological damage, interstitial inflammation, and fibrosis. Age-matched female NAME rats showed significantly lower albuminuria, diminished glomerular ischemia, and glomerulosclerosis, as well as a significant reduction in the expression of α-smooth muscle actin renal interstitial Ang II+ cells. Thus, the present study demonstrated that female rats submitted to the NAME model developed less severe CKD than males. Female renoprotection could be promoted by both the estrogen anti-inflammatory activity and/or by the lack of testosterone, related to renin-angiotensin-aldosterone system hyperactivation and fibrogenesis. However, the influence of sex hormones on the progression of CKD needs to be further investigated.

Asunto(s)

Glomérulos Renales , NG-Nitroarginina Metil Éster/efectos adversos , Óxido Nítrico/antagonistas & inhibidores , Insuficiencia Renal Crónica , Caracteres Sexuales , Animales , Femenino , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos

RESUMEN

BACKGROUND: The search for risk factors for chronic kidney disease in children with focal segmental glomerulosclerosis (FSGS) is important in defining prognosis and individualized treatment. This study preliminarily investigated whether CD44 immunostaining in glomerular parietal epithelial cells (PECs) is a prognostic marker in pediatric FSGS. METHODS: In this retrospective study, 26 patients with FSGS, biopsied from 1985 to 2010, were evaluated. Immunohistochemistry for CD44 was performed in all cases. For analysis purposes, patients were grouped according to whether or not they were positive for CD44 in PECs. The primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) of 50% or more. RESULTS: Median follow-up was 6.9 years. Median renal survival was 14.5 years and probability of a 50% decline of eGRF was 30% in 10 years. Nine children exhibited the primary outcome and 7 developed end-stage renal disease (ESRD). In comparison with PEC CD44-negative patients (n = 18), PEC CD44-positive patients (n = 8) presented lower baseline eGFR (99 ± 41 versus 141 ± 44 ml/min/1.73 m2, p = 0.035) and a significant decline in eGFR (-38.6 ± 39.5 versus -5.6 ± 25.3 ml/min/1.73 m2/year, p = 0.018). No difference was observed in FSGS subtypes or other glomerular features. Presence of CD44 staining in PECs was significantly associated with the decline in baseline eGFR of 50% or more. Renal survival was significantly reduced in PEC CD44-positive patients (3.8 vs 14.6 years in C4d-negative, p < 0.05). CONCLUSION: Our preliminary findings indicate, for the first time, that positivity for CD44 in PECs seems to be a pathological marker of renal function deterioration in pediatric patients with FSGS.

Asunto(s)

Biomarcadores/metabolismo , Glomeruloesclerosis Focal y Segmentaria/patología , Receptores de Hialuranos/metabolismo , Glomérulos Renales/patología , Adolescente , Niño , Preescolar , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Femenino , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Humanos , Inmunohistoquímica , Fallo Renal Crónico/etiología , Glomérulos Renales/metabolismo , Masculino , Estudios Retrospectivos , Análisis de Supervivencia

RESUMEN

BACKGROUND: Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. STUDY DESIGN: Case series. SETTINGS & PARTICIPANTS: In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m2. Exclusion criteria were proteinuria with protein excretion > 3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. OUTCOMES: Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. MEASUREMENTS: eGFR was calculated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C (eGFRcr-cys) equations. RESULTS: In the kidney biopsy study, participants had a mean eGFRcr of 57 (range, 33-96) mL/min/1.73m2. 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFRcr was -4.4±8.4 (range, -27.7 to 10.2) mL/min/1.73m2 per year. Most patients had stopped working with sugarcane cultivation. LIMITATIONS: 3 biopsy specimens had 4 or fewer glomeruli. CONCLUSIONS: This study confirms the renal morphology of MeN: chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia. Follow-up data show that eGFRs, on average, deteriorated.

Asunto(s)

Tasa de Filtración Glomerular , Glomérulos Renales/patología , Insuficiencia Renal Crónica/patología , Lesión Renal Aguda , Adulto , América Central/epidemiología , Creatinina/metabolismo , Cistatina C/metabolismo , Progresión de la Enfermedad , El Salvador , Enfermedades Endémicas , Agricultores , Estudios de Seguimiento , Calor , Humanos , Hipertrofia , Hipopotasemia/epidemiología , Hipopotasemia/metabolismo , Hiponatremia/epidemiología , Hiponatremia/metabolismo , Hipovolemia , Biopsia Guiada por Imagen , Isquemia , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/metabolismo , Glomérulos Renales/fisiopatología , Masculino , Persona de Mediana Edad , Nicaragua/epidemiología , Exposición Profesional , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Población Rural , Saccharum , Esclerosis , Ultrasonografía , Desequilibrio Hidroelectrolítico , Adulto Joven

RESUMEN

OBJECTIVE: This work aimed to study the effect of uteroplacental circulation restriction on endothelial kidney damage in a fetal rabbit model. METHODS: New Zealand rabbits were subjected to 40% to 50% of uteroplacental artery ligation at day 25 of pregnancy. After 5 days, surviving fetuses were harvested by cesarean section. The gene and protein expressions of selected enzymes associated with nitric oxide production and oxidative stress were analyzed in fetal kidney homogenates. RESULTS: The placenta weight (6.06 ± 0.27, p < 0.0319) and fetal body (19.90 ± 1.03, p < 0.0001) were significantly reduced in the uteroplacental circulation restriction group. The kidneys from restricted fetuses presented a mild vascular congestion and glomerular capillary congestion, without inflammation or hypertrophy. We found endothelial nitric oxide synthase phosphorylation inhibition (0.23 ± 0.13, p < 0.012) and arginase-2 (0.29 ± 0.14, p < 0.023) protein induction in fetal kidneys of the circulation restriction group. Finally, the kidneys from circulation-restricted fetuses showed increased inducible nitric oxide synthase messenger RNA (mRNA) (2.68 ± 0.24, p < 0.01) and reduced heme oxygenase-1 mRNA (23 ± 1.3, p < 0.003), with increased reactive oxygen species (1.69 ± 0.09, p < 0.001) and nitrotyrosine protein (1.74 ± 0.28, p < 0.003) levels, without changes in Nox mRNA. CONCLUSION: We describe significant deregulation of vascular activity and oxidative damage in kidneys of fetal rabbits that have been exposed to restriction of the uterine circulation. © 2016 John Wiley & Sons, Ltd.

Asunto(s)

Arginasa/metabolismo , Retardo del Crecimiento Fetal/genética , Hemo-Oxigenasa 1/genética , Glomérulos Renales/metabolismo , Óxido Nítrico Sintasa/genética , Estrés Oxidativo/genética , Animales , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/metabolismo , Hemo-Oxigenasa 1/metabolismo , Riñón/metabolismo , Riñón/patología , Glomérulos Renales/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Circulación Placentaria , Embarazo , ARN Mensajero/metabolismo , Conejos , Especies Reactivas de Oxígeno/metabolismo , Transcriptoma , Tirosina/análogos & derivados , Tirosina/metabolismo

RESUMEN

Renal development in rodents, unlike in humans, continues during early postnatal period. We aimed to evaluate whether the pharmacological inhibition of Endothelin system during this period affects renal development, both at structural and functional level in male and female rats. Newborn rats were treated orally from postnatal day 1 to 20 with vehicle or bosentan (Actelion, 20 mg/kg/day), a dual endothelin receptor antagonist (ERA). The animals were divided in 4 groups: control males, control females, ERA males and ERA females. At day 21, we evaluated renal function, determined the glomerular number by a maceration method and by morphometric analysis and evaluated possible structural renal alterations by three methods: 〈alpha〉-Smooth muscle actin (α-SMA) immunohistochemistry, Masson's trichrome and Sirius red staining. The pharmacological inhibition of Endothelin system with a dual ERA during the early postnatal period of the rat did not leads to renal damage in the kidneys of male and female rats. However, ERA administration decreased the number of glomeruli, the juxtamedullary filtration surface area and the glomerular filtration rate and increased the proteinuria. These effects could predispose to hypertension or renal diseases in the adulthood. On the other hand, these effects were more pronounced in male rats, suggesting that there are sex differences that could be greater later in life. These results provide evidence that Endothelin has an important role in rat renal postnatal development. However these results do not imply that the same could happen in humans, since human renal development is complete at birth.

Asunto(s)

Antagonistas de los Receptores de Endotelina/farmacología , Endotelinas/fisiología , Glomérulos Renales/crecimiento & desarrollo , Sulfonamidas/farmacología , Animales , Bosentán , Femenino , Tasa de Filtración Glomerular , Riñón/citología , Riñón/efectos de los fármacos , Riñón/crecimiento & desarrollo , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Masculino , Ratas Sprague-Dawley , Receptores de Endotelina/metabolismo

RESUMEN

After years of discussion by the Chilean legislature, the Law Nº 20.584, which regulates health care related rights and duties of people, entered into force in Chile in October 2012. This bill represents an important step in the recognition and protection of health care related rights, welfare, dignity and duties of persons. It also intends to protect potential participants in clinical research. However such protective measures include explicit prohibitions such as the review of clinical records or the inclusion of people with mental or psychological handicaps as research participants. We herein discuss the implications of this law in medical research.

Asunto(s)

Animales , Masculino , Ratas , Regulación de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Modelos Animales de Enfermedad , Glomerulonefritis/metabolismo , Hipertensión/patología , Glomérulos Renales/metabolismo , Túbulos Renales/metabolismo , Riñón/lesiones , Riñón/metabolismo , Ratas Endogámicas WKY , Factores de Tiempo , Factor de Crecimiento Transformador beta/metabolismo , Uréter/patología

RESUMEN

The chemotherapeutic drug cisplatin has some side effects including nephrotoxicity that has been associated with reactive oxygen species production, particularly superoxide anion. The major source of superoxide anion is nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase. However, the specific segment of the nephron in which superoxide anion is produced has not been identified. Rats were sacrificed 72 h after cisplatin injection (7.5 mg/kg), and kidneys were obtained to isolate glomeruli and proximal and distal tubules. Cisplatin induced superoxide anion production in glomeruli and proximal tubules but not in distal tubules. This enhanced superoxide anion production was prevented by diphenylene iodonium, an inhibitor of NADPH oxidase. Consistently, this effect was associated with the increased expression of gp91(phox) and p47(phox), subunits of NADPH oxidase. The enhanced superoxide anion production in glomeruli and proximal tubules, associated with the increased expression of gp91(phox) and p47(phox), is involved in the oxidative stress in cisplatin-induced nephrotoxicity.

Asunto(s)

Antineoplásicos/toxicidad , Cisplatino/toxicidad , Glomérulos Renales/efectos de los fármacos , Túbulos Renales Proximales/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasas/metabolismo , Superóxidos/metabolismo , Animales , Glomérulos Renales/metabolismo , Túbulos Renales Proximales/metabolismo , Masculino , NADPH Oxidasa 2 , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar

RESUMEN

The role of albumin overload in proximal tubules (PT) in the development of tubulointerstitial injury and, consequently, in the progression of renal disease has become more relevant in recent years. Despite the importance of leukotrienes (LTs) in renal disease, little is known about their role in tubulointerstitial injury. The aim of the present work was to investigate the possible role of LTs on tubulointerstitial injury induced by albumin overload. An animal model of tubulointerstitial injury challenged by bovine serum albumin was developed in SV129 mice (wild-type) and 5-lipoxygenase-deficient mice (5-LO(-/-)). The changes in glomerular morphology and nestin expression observed in wild-type mice subjected to kidney insult were also observed in 5-LO(-/-) mice. The levels of urinary protein observed in the 5-LO(-/-) mice subjected or not to kidney insult were lower than those observed in respective wild-type mice. Furthermore, the increase in lactate dehydrogenase activity, a marker of tubule damage, observed in wild-type mice subjected to kidney insult did not occur in 5-LO(-/-) mice. LTB4 and LTD4, 5-LO products, decreased the uptake of albumin in LLC-PK1 cells, a well-characterized porcine PT cell line. This effect correlated with activation of protein kinase C and inhibition of protein kinase B. The level of proinflammatory cytokines, tumor necrosis factor-α and interleukin (IL)-6, increased in mice subjected to kidney insult but this effect was not modified in 5-LO(-/-) mice. However, 5-LO(-/-) mice subjected to kidney insult presented lower macrophage infiltration and higher levels of IL-10 than wild-type mice. Our results reveal that LTs have an important role in tubulointerstitial disease induced by albumin overload.

Asunto(s)

Araquidonato 5-Lipooxigenasa/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Túbulos Renales Proximales/patología , Proteinuria/complicaciones , Proteinuria/metabolismo , Albúmina Sérica/metabolismo , Animales , Araquidonato 5-Lipooxigenasa/genética , Bovinos , Línea Celular , Modelos Animales de Enfermedad , Eliminación de Gen , Enfermedades Renales/genética , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Túbulos Renales Proximales/metabolismo , Masculino , Ratones , Proteinuria/genética , Porcinos

RESUMEN

BACKGROUND: Heparanase-1 activation, albuminuria, and a decrease in glomerular heparan sulfate (HS) have been described in diabetic nephropathy (DN). Glycosaminoglycan (GAG)-based drugs have been shown to have renoprotective effects in this setting, although recent trials have questioned their clinical effectiveness. Here, we describe the effects of fucosylated chondroitin sulfate (FCS), a novel GAG extracted from a marine echinoderm, in experimentally induced DN compared to a widely used GAG, enoxaparin (ENX). METHODS: Diabetes mellitus (DM) was induced by streptozotocin in male Wistar rats divided into three groups: DM (without treatment), FCS (8 mg/kg), and ENX (4 mg/kg), administered subcutaneously. After 12 weeks, we measured blood glucose, blood pressure, albuminuria, and renal function. The kidneys were evaluated for mesangial expansion and collagen content. Immunohistochemical quantifications of macrophages, TGF-ß, nestin and immunofluorescence analysis of heparanase-1 and glomerular basement membrane (GBM) HS content was also performed. Gene expression of proteoglycan core proteins and enzymes involved in GAG assembly/degradation were analyzed by TaqMan real-time PCR. RESULTS: Treatment with GAGs prevented albuminuria and did not affect the glucose level or other functional aspects. The DM group exhibited increased mesangial matrix deposition and tubulointerstitial expansion, and prevention was observed in both GAG groups. TGF-ß expression and macrophage infiltration were prevented by the GAG treatments, and podocyte damage was halted. The diabetic milieu resulted in the down-regulation of agrin, perlecan and collagen XVIII mRNAs, along with the expression of enzymes involved in GAG biosynthesis. Treatment with FCS and ENX positively modulated such changes. Heparanase-1 expression was significantly reduced after GAG treatment without affecting the GBM HS content, which was uniformly reduced in all of the diabetic animals. CONCLUSIONS: Our results demonstrate that the administration of FCS prevented several pathological features of ND in rats. This finding should stimulate further research on GAG treatment for this complication of diabetes.

Asunto(s)

Sulfatos de Condroitina/farmacología , Sulfatos de Condroitina/uso terapéutico , Citoprotección/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Riñón/efectos de los fármacos , Albuminuria/metabolismo , Animales , Colágeno/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Glicosaminoglicanos/farmacología , Glicosaminoglicanos/uso terapéutico , Riñón/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Ratas , Ratas Wistar , Estreptozocina