Mitochondria and oxidative stress participation in renal inflammatory process

La muerte celular programada y fibrosis renal son procesos inherentes a la enfermedad renal crónica, y en tal sentido ha sido recientemente descripto, una clara desregulación de la maquinaria respiratoria mitocondrial en pacientes con enfermedad renal crónica asociada con un aumento del estrés oxidativo. Las células tubulares lesionadas vinculadas a los macrófagos intersticiales, y miofibroblastos producen citoquinas y factores de crecimiento que promueven un estado inflamatorio, inducen la apoptosis de las células tubulares y facilitan la acumulación de matriz extracelular. La angiotensina II desempeña un papel central en la fibrogénesis renal y conduce a una rápida progresión de la enfermedad renal crónica. Los niveles crecientes de la angiotensina II inducen citoquinas pro-inflamatorias, la activación de NF-kB, moléculas de adhesión, quimiocinas, factores de crecimiento, y el estrés oxidativo. Toda la evidencia actual sugiere que angiotensina II aumenta el estrés oxidativo mitocondrial, regula la inducción de apoptosis y condiciona al estado inflamatorio. Por lo tanto, existiría un papel determinante de las mitocondrias y el estrés oxidativo en el proceso inflamatorio renal. Finalmente, esta revisión resume nuestro actual conocimiento acerca de los posibles mecanismos que contribuirían con la apoptosis modulada por la inflamación y/o el estrés oxidativo durante la enfermedad renal crónica. Además, se propone un nuevo concepto de herramientas anti-inflamatorias que regulan el estrés oxidativo mitocondrial lo cual afectaría directamente al proceso inflamatorio y la apoptosis. Esta idea podría tener consecuencias atractivas sobre el tratamiento de patologías inflamatorias renales y de otras afines.Mitochondria and oxidative stress participation in renal inflammatory process. The apoptosis and renal fibrosis are processes inherent to the chronic kidney disease, and consequently a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with chronic renal disease associated to an increase of the oxidative stress. The injured tubular cells linked to the interstitial macrophages and myofibroblasts produce cytokines and growth factors that encourage an inflammatory condition, inducing the apoptosis of the tubular cells and enabling the accumulation of the extracellular matrix. The angiotensin II has a central role in the renal fibrogenesis leading to a rapid progression of the chronic kidney disease. The growing levels of the angiotensin II induce pro-inflammatory cytokines, the activation of NF-kB, adhesion molecules,chemokines, growth factors, and oxidative stress. The current evidence suggests that the angiotensin II increases the mitochondrial oxidative stress, regulates the induction of the apoptosis and conditions the inflammatory process. Therefore the mitochondria and the oxidative stress would play a determinant role in the renal inflammatory process. Finally, this review summarizes our present knowledge regarding the possible mechanisms that would contribute to the apoptosis conditioned by inflammation and/or oxidative stress during the chronic renal disease. Additionally, a new concept of the anti-inflammatory tools is proposed to regulate the mitochondrial oxidative stress that would directly affect the inflammatory process and apoptosis. This concept could have positive consequences on the treatment of renal inflammatory pathologies and related diseases.Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Departamento de Patología; Argentin

Patrón génico de fibrosis y apoptosis en nefropatía obstructiva experimental : : modulación por rosuvastatina

La nefropatía obstructiva puede ser un desorden renal complejo de tratar debido al severo cuadro inflamatorio, desbalance oxidativo, apoptosis y fibrosis. Estudios previos sostienen que rosuvastatina (Ros) podría tener utilidad como una opción terapéutica en enfermedades renales que cursarían con apoptosis y fibrosis. Objetivo: Evaluar los posibles efectos antiapoptóticos y antifibróticos de Ros durante la obstrucción ureteral unilateral en ratas neonatas. Materiales y Métodos: Ratas Wistar neonatas de 48 hs. de vida fueron intervenidas quirúrgicamente (grupo experimental) o no (grupo control). Ambos grupos fueron subdivididos en tratadas o no tratadas con Ros (10mg / kg por día) vía oral durante 14 días. Posteriormente se procedió a nefrectomizar y procesar las cortezas renales para determinar por RT-PCR las expresiones de genes: óxido nítrico sintasa inducible (iNOS), factor promotor génico de chaperonas (hsf1), proteína de shock térmico (hsp70), bax, bcL2, wt1, p53, snail, proteína morfogénica del hueso (bmp7), caderina E, factor transformador de crecimiento (tgf-β) y factor de necrosis tumoral (tnf-α). Resultados: La obstrucción ureteral unilateral neonatal indujo una marcada fibrosis y apoptosis, mientras que el tratamiento con Ros moduló el patrón de genes fibróticos y apoptóticos mediante disminución de la expresión de bmp7, caderina E, wt1, p53 y bcl2; además indujo una caída en la expresión de los genes profibróticos y proapoptóticos (bax, tnf-α y tgf-β). El análisis de los resultados presentados, permiten sugerir que la protección renal de rosuvastatina durante nefropatía obstructiva de ratas neonatas estaría asociado a la interacción entre hsp70 y la biodisponibilidad del óxido nítrico con el concomitante descenso en genes pro-apoptóticos.Fibrosis and apoptosis gene pattern in experimental obstructive nephropathy: Rosuvastatin modulation Obstructive nephropathy renal disorder can be complex to treat due to the severe apoptosis and fibrosis. Previous studies shown that rosuvastatin (Ros), may have potential utility as a therapeutic option in kidney diseases which lead to apoptosis and fibrosis. Objective: to evaluate the possible antifibrotic and antiapoptotic effects of Ros during experimental neonatal rats unilateral ureteral obstruction (UUO). Materials and Methods: Neonatal rats were surgically obstructed (experimental group) or not (control group), which were Ros treated or not (10 mg/kg per day) during 14 days. Subsequent nephrectomy and processing of the renal cortex to determinate by RT-PCR technique, genes expression of inducible nitric oxide synthase (iNOS), heat shock factor 1 (hsf1), heat shock protein 70 (hsp70), bax, bcl2, wt1, p53, snail, bone morphogenetic protein (bmp7), E-cadherin, transforming growth factor (tgf-β) and tumor necrosis factor (tnf-α). Results: neonatal UUO induced fibrosis and apoptosis, while Ros treatment modulated the fibrotic and apoptotic genes pattern and increased the bmp7, Ecadherin, wt1, p53 and bcl2 expression as well as decreased the profibrotic and proapoptotic genes expression (bax, tnf-α y tgf-β). Our results allow us to suggest that Ros renal protection during UUO is linked to hsp70 and nitric oxide bioavailability interaction, with concomitant decrease in pro apoptotic gene pattern.Fil: Mazzei, L.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Área de FisiopatologíaFil: García, M.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Área de FisiopatologíaFil: Manucha, W.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Área de Fisiopatologí

Efectos pleotrópicos de inhibidores de 3-hidroxi-3-metilglutaril-coa reductasa en nefropatía obstructiva

The incidence of chronic renal diseases is increasing world-wide, and there is a great need to identify therapies capable of arresting or reducing disease progression. The current treatment of chronic nephropathies is limited to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but there is growing clinical and experimental evidence that statins (3-hydroxy-3-methyglutaryl-CoA reductase inhibitors) could play a therapeutic role.Fil: Kurbán Carosella, Fernando Tufik. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentin

WT-1 Expresion linked to nitric oxide availability during neonatal obstructive nephropathy

The wt-1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context. The wt-1 regulates the expression of a large number of genes that have a critical role in kidney development. Congenital obstructive nephropathy disrupts normal renal development and causes chronic progressive interstitial fibrosis, which contributes to renal growth arrest, ultimately leading to chronic renal failure. Wt-1 is downregulated during congenital obstructive nephropathy, leading to apoptosis. Of great interest, nitric oxide bioavailability associated with heat shock protein 70 (Hsp70) interaction may modulate wt-1 mRNA expression, preventing obstruction-induced cell death during neonatal unilateral ureteral obstruction. Moreover, recent genetic researches have allowed characterization of many of the complex interactions among the individual components cited, but the realization of new biochemical, molecular and functional experiments as proposed in our and other research labs, allow us to establish a deeper level of commitment among proteins involved and the potential pathogenic consequences of their imbalance.Fil: Mazzei, Luciana Jorgelina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médica; Argentin

El factor de la trasncripción WT-1 y su relación con el desarrollo de la injuria renal inducida durante la nefropatía obstructiva

El estudio del desarrollo renal sirve como un paradigma para comprender los mecanismos que son la base de la formación de un órgano. Múltiples genes desempeñan funciones trascendentes en el desarrollo renal temprano, entre los que se destaca WT-1. Se ha comprobado experimentalmente que la proteína WT1 en unos casos reprime y en otros activa la transcripción de numerosos genes, pero sus dianas fisiológicas son poco conocidas. Recientes investigaciones genéticas han permitido caracterizar muchas de las complejas interacciones entre los componentes individuales, sin embargo la concreción de nuevos experimentos bioquímicos, moleculares y funcionales como los propuestos en nuestro y otros laboratorios de investigación, nos permitirán establecer con mayor profundidad el grado de compromiso entre las proteínas participantes y las posibles consecuencias fisiopatogénicas de su desacopleFil: Mazzei, Luciana Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Manucha, Walter Ariel Fernando. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Medicina y Biologia Experiment.de Cuyo; Argentin

Changes in renal WT-1 expression preceding hypertension development

Background: Hypertension is a public health problem with mostly unknown causes, and where strong hereditary genetic alterations have not been fully elucidated. However, the use of experimental models has provided valuable information. Recent evidences suggest that alterations in key nephrogenic factors, such as Wilms' tumor 1 transcription factor (WT-1), could contribute to the development of hypertension. The aim of this paper is to evaluate the expression of WT-1 and related genes in the nephrogenic process in connection with the development of hypertension as well as the corresponding anatomical and functional correlation. Methods: Male spontaneously hypertensive and control rats were evaluated weekly from birth until week 8 of life. Their blood pressure was taken weekly using the tail-cuff blood pressure system. Weekly, 5 rats per group were sacrificed with a lethal injection of pentobarbital, and their kidneys were removed, decapsulated and weighed. The serum was collected for measuring biochemical parameters. The results were assessed using one-way analysis of variance for comparisons between groups. Results: The relationship between renal weight/total body weights was established, without significantly different values. These data were compared with apoptosis, fibrosis, number and size of the glomeruli. The elevation of systolic blood pressure was significant since week 6. Biochemical values differed slightly. Histology showed a slight increase in deposits of collagen fibers since week 4. Additionally, in kidney cortices, the expression of WT-1, heat shock protein 70 (Hsp70) and vitamin D receptors (VDR) decreased since week 4. Finally, we demonstrated ultrastructural damage to mitochondria since week 4. Conclusions: Our results would suggest an unprecedented link, possibly a regulatory mechanism, between WT-1 on nephrogenic alteration processes and their relationship with hypertension. Moreover, and previous to the increase in blood pressure, we demonstrated low expressions of WT-1, VDR and Hsp70 in kidneys from neonatal SHRs. If so, this may suggest that deregulation in the expression of WT-1 and its impact on nephrogenesis induction could be crucial in understanding the development and maintenance of hypertension.Fil: Mazzei, Luciana Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: García, Isabel Mercedes. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Calvo, Juan Pablo. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Casarotto, Mariana. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Fornes, Miguel Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Abud, María Angélica. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ferder, León. Universidad de Puerto Rico; Puerto RicoFil: Manucha, Walter Ariel Fernando. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

The world pandemic of vitamin D deficit culd possibly be explained by cellular inflammatory response activity induced by the renin angiotensin system

This review attempts to show that there may be a relationship between inflammatory processes induced by chronic overstimulation of the renin-angiotensin system (RAS) and the worldwide deficiency of vitamin D (VitD) and that both disorders are probably associated with environmental factors. Low VitD levels represent a risk factor for several apparently different diseases, such as infectious, autoimmune, neurodegenerative, and cardiovascular diseases, as well as diabetes, osteoporosis, and cancer. Moreover, VitD insufficiency seems to predispose to hypertension, metabolic syndrome, left ventricular hypertrophy, heart failure, and chronic vascular inflammation. On the other hand, inappropriate stimulation of the RAS has also been associated with the pathogenesis of hypertension, heart attack, stroke, and hypertrophy of the left ventricle and vascular smooth muscle cells. Because VitD receptors (VDRs) and RAS receptors are almost distributed in the same tissues, a possible link between VitD and the RAS is even more plausible. Furthermore, from an evolutionary point of view, both systems were developed simultaneously, actively participating in the regulation of inflammatory and immunological mechanisms. Changes in RAS activity and activation of the VDR seem to be inversely related; thus any changes in one of these systems would have a completely opposite effect on the other, making it possible to speculate that the two systems could have a feedback relationship. In fact, the pandemic of VitD deficiency could be the other face of increased RAS activity, which probably causes lower activity or lower levels of VitD. Finally, from a therapeutic point of view, the combination of RAS blockade and VDR stimulation appears to be more effective than either RAS blockade or VDR stimulation individually.Fil: Ferder, Marcelo. Universidad de Buenos Aires. Facultad de Medicina; Argentina;Fil: Inserra, Pablo Ignacio Felipe. Universidad Austral. Facultad de Cs.biomedicas; Argentina;Fil: Manucha, Walter Ariel Fernando. Universidad Nacional de Cuyo; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina;Fil: Ferder, León. Ponce School of Medicine and Health Sciences; Puerto Rico

Unintended Plagiarism Amongst International Students in Western Universities

In recent years, many western universities have experienced a notable increase of plagiarism and other behaviors that fall under the umbrella of academic dishonesty amongst students at various levels. Concurrently, higher-educational institutions have also seen a large rise in the enrollment of international students with extremely diverse cultural and linguistic backgrounds. A growing body of research has connected higher rates of plagiarism, in western universities during this time period, to international students in particular. This article reviews the current literature in this area, with a focus on the most common factors that put international students in western universities at a higher risk for unintended plagiarism than their counterpart domestic peers. The results showcase a complex myriad of factors that put international students at risk, such as new cultural, financial, or time stresses; underdeveloped language skills; the inability to self-advocate; and cultural differences in both schooling systems and viewing sources. Considering these factors, several practical implementations are recommended for institutions of higher education, with the aim of lessening international students’ risk factors of unintentional plagiarism, while simultaneously building academic confidence and community

Histiocytic Sarcoma in a Kidney Transplant Patient: A Case Report and Review of the Literature

Objective. Histiocytic sarcoma (HS) is an aggressive neoplasm with only limited number of reported series of cases and rare case reports of occurrence as a posttransplant neoplastic disorder. The etiology and pathogenesis of the disease is unknown and the optimal treatment is still under investigation. We describe an unusual case of HS in a patient with a remote history of kidney transplant. Method and Results. A 54-year-old male with a remote history of renal transplantation under maintenance immunosuppression presented with features of sepsis. CT abdomen revealed multiple heterogeneous masses in bilateral native kidneys and liver and enlarged abdominal and retroperitoneal lymph nodes. Viral serology work-up was negative. Needle core biopsy revealed a highly undifferentiated neoplasm comprised of highly atypical large cells with eosinophilic to vacuolated cytoplasm and hemophagocytosis. Extended panel of immunohistochemistry proved histiocytic lineage for the tumor cells. The patient expired 2 weeks following the diagnosis. Conclusion. Our case along with three previously published case reports raised the possibility of HS as a treatment-related neoplasm or a posttransplantation neoplastic disorder in solid organ transplant recipients