Pathogenesis of Minimal Change Nephrotic Syndrome: A Review of the Underlying Molecular Mechanisms

Nephrotic syndrome (NS) is the most common glomerular disorder in childhood, and a vast majority of cases are idiopathic. The precise cause of this common childhood disease is not fully elucidated despite significant advancements in our understanding of podocyte biology. Idiopathic NS has been considered “a disorder of T-cell function” mediated by a circulating factor that alters podocyte function resulting in massive proteinuria since the last four decades. Several circulatory factors released from T-cells are considered to be involved in pathophysiology of NS; however, a single presumptive factor has not been defined yet. Extended evidence obtained by advances in the pathobiology of podocytes has implicated podocytes as critical regulator of glomerular protein filtration and podocytopathy. The candidate molecules as pathological mediators of steroid-dependent NS are CD80 (also known as B7-1), hemopexin, and angiopoietin-like 4. The “two-hit” hypothesis proposes that the expression of CD80 on podocytes and ineffective inhibition of podocyte CD80 due to regulatory T-cell dysfunction or impaired autoregulation by podocytes results in NS. Recent studies suggest that not only T cells but also other immune cells and podocytes are involved in the pathogenesis of MCNS.

Subprodutos do metabolismo da hemoglobina se associam com resposta inflamatória em pacientes com acidente vascular cerebral hemorrágico / Hemoglobin metabolism by-products are associated with an inflammatory response in patients with hemorrhagic stroke

RESUMO Objetivo: Avaliar o relacionamento entre os níveis cerebrais de ferro e heme e a resposta inflamatória sistêmica e no sistema nervoso central, assim como o papel dos sistemas de defesa contra a toxicidade do ferro e do heme, no sistema nervoso central. Métodos: Avaliamos uma coorte prospectiva de pacientes com quadro de hemorragia intracraniana e subaracnóidea. Realizamos ensaios em amostras de plasma e líquido cefalorraquidiano quanto à presença de ferro, heme, hemopexina, haptoglobina, enolase, S100-β e citocinas nos primeiros 3 dias após um acidente vascular cerebral hemorrágico. Analisamos também as alterações dinâmicas em todos os componentes de ambos os líquidos e seu relacionamento com as taxas de mortalidade precoce. Resultados: As concentrações de hemopexina e haptoglobina foram quase desprezíveis no cérebro após hemorragia intracraniana e subaracnóidea. As concentrações de ferro e heme no líquido cefalorraquidiano se correlacionaram com resposta pró-inflamatória no sistema nervoso central, e os perfis inflamatórios no líquido cefalorraquidiano no terceiro dia após acidente vascular cerebral hemorrágico se correlacionaram com as taxas de mortalidade precoce. Identificamos que os níveis de interleucina 4 no líquido cefalorraquidiano durante as primeiras 24 horas após acidente vascular cerebral hemorrágico foram mais altos nos sobreviventes do que nos que não sobreviveram. Conclusão: Os níveis de ferro e heme se associaram com resposta pró-inflamatória no sistema nervoso central após acidente vascular cerebral hemorrágico, e o cérebro humano não tem proteção contra hemoglobina e heme. Os perfis inflamatórios dos pacientes se associaram com prognósticos piores, e as respostas inflamatórias locais pareceram ter um papel protetor.

ABSTRACT Objective: To evaluate the relationships of brain iron and heme with the inflammatory response of the systemic and central nervous systems and to investigate the role of defensive systems against the toxicity of iron and heme in the central nervous system. Methods: We assessed a prospective cohort of patients presenting with intracerebral and subarachnoid hemorrhage. We assayed plasma and cerebrospinal fluid samples for the presence of iron, heme, hemopexin, haptoglobin, enolase, S100-β and cytokines for the first three days following hemorrhagic stroke. We also analyzed the dynamic changes in these components within both fluids and their relationship with early mortality rates. Results: Hemopexin and haptoglobin concentrations were nearly negligible in the brain after intracerebral and subarachnoid hemorrhage. Cerebrospinal fluid iron and heme concentrations correlated with a pro-inflammatory response in the central nervous system, and plasmatic and cerebrospinal fluid inflammatory profiles on the third day after hemorrhagic stroke were related to early mortality rates. Interleukin 4 levels within the cerebrospinal fluid during the first 24 hours after hemorrhagic stroke were found to be higher in survivors than in non-survivors. Conclusion: Iron and heme are associated with a pro-inflammatory response in the central nervous system following hemorrhagic stroke, and protections against hemoglobin and heme are lacking within the human brain. Patient inflammatory profiles were associated with a poorer prognosis, and local anti-inflammatory responses appeared to have a protective role.

Progress in biochemical characteristics of hemopexin and its clinical application / 中国实验血液学杂志

Hemopexin (HPX) is a plasma protein with the strongest binding capacity to heme and widely involved in modulation of a variety of physiological and pathological processes. The main physiological function of HPX is to bind and transport free toxic heme. Recent studies indicate that HPX also plays roles of anti-oxidant, anti-apoptosis, immune regulation and organic protection. In addition, HPX participates in regulation of cell differentiation and extracellular matrix reconstruction. In recent years, a great deal of progress has been made in studies of the mechanisms of HPX protective effects and on possible clinical application. In the past few years, especially, a number of proteomic studies have demonstrated that HPX could be served as positive molecular biomarkers for cancers of lung, liver, kidney, colon, and uterine myoma as well as osteoarthritis. In this review, recent progress in the biochemical characteristics and function of HPX and its possible clinical applications are summarized.

Hemin inhibits lipid peroxidation induced by ascorbate/FeSO4 and 2,2'-azobis-2-amidino-propane hydrochloride (ABAP)

Hemin blocked lipid peroxidations induced by either ascorbate/FeSO4, a metal-catalyzed oxidation system, or 2,2'-azobis-2-amidino-propane hydrochloride (ABAP) which produces peroxy radicals at constant rates. Hemin at very low micromolar concentrations strongly inhibited the ascorbate/FeSO4-induced peroxidation of rat liver phopholipids, soybean phosphatidylcholine and arachidonic acid, and this inhibition was also evident with the use of ABAP, although much higher concentrations of hemin were required than those for the inhibition of ascorbate/FeSO4-induced lipid peroxidation. However, hemoproteins such as hemoglobin, myoglobin and cytochrome C did not show any significant effect on this lipid peroxidation. Hemopexin and albumin abolished the inhibitory action of hemin. During incubation with ascorbate/FeSO4 or ABAP, hemin underwent a change in its absorption spectrum, resulting in a progressive decrease in the peak height of the characteristic absorption band at 385 nm. The above results suggest that hemin may act as an important antioxidant in vivo, protecting lipids from the peroxidative damage.

Detection rates for Duchenne muscular dystrophy gene cariers using logistic discrimination: creatine-kinase and hemopexin

Foram determinados os níveis de creatino-cinase (CK) e de hemopexina ( H) em 117 amostras de soro: 59 de portadoras certas do gene da distrofia muscular Duchenne (DMD) e 58 de 30 mulheres adultas normais. Nosso objetivo foi determinar a eficácia de cada proteína isoladamente e das duas em combinaçäo na identificaçäo de portadoras do gene da DMD. Considerando as características de nossas duas amostras de mulheres quanto às medidas de CK e de YH, escolhemos o modelo logístico de análise discriminante como o mais adequado. A CK e a H, cada uma isoladamente, apresentaron 82 e 59%, respectivamente, de eficácia na detecçäo de heterozigotas para o gene da DMD, isto é houve 18 e 41% de erros de classificaçäo na identificaçäo de portadoras certas do gene da DMD quando estas duas proteínas foram consideradas separadamente. A combinaçäo da CK com a H mostrou uma eficácia de 88%, isto é, os erros de classificaçäo no grupo de heterozigotas para o gene da DMD foram reduzidos de 18 para 12%, mas esta diferença näo se mostrou estadisticamente significativa. Assim, a combinaçäo da CK com a H näo melhorou a detecçäo quando comparada com o uso da CK isoladamente

Hemopexina e inmunoglobulinas en las ascitis benignas y malignas: experiencia en 66 pacientes / Hemopexin and inmunoglobins in benign and malign ascites: experience in 66 patients

Se estudiaron 66 pacientes con ascitis de distintas etiologías efectuando el examen proteico inmunoelectroforético de sus sueros y líquidos peritoneales y la determinación de hemopexina en estos últimos. Las inmunoglubulinas pueden presentar valores elevados en los derrames de naturaleza neoplásica, especialmente IgG e IgA. Las determinaciones más altas, sin embargo, se hallaron en aquellos de las insuficiencias cardíacas congestivas. Los cocientes obtenidos de la relación inmunoglobulina ascitis/inmunoglubulina sérica son útiles desde el punto de vista estadístico, aunque su valor práctico es limitado. No se observó correlación plasma/ascitis en los enfermos cirróticos ni en los neoplásicos. La cuantificación de Hemopexina demostró, por sí sola, ser concluyente en el diagnóstico diferencial. El 100% de las ascitis benignas (cirrosis, insuficiencia cardíaca congestiva e insuficiencia renal) presentaron valores inferiores a 170 mg/dl, mientras que el 90.5% de los pacientes neoplásicos arrojaron cifras superiores a dicho valor. La media para los cirróticos fue de 30.79 ñ 5.31 mg/dl y para los neoplásicos de 205.19 ñ 9.62 mg/dl con una diferencia para ambos grupos estadísticamente significativa (p < 0.001). Su determinación podría indicar, con una alta probabilidad, la etiología del proceso. No sólo sirvió en los casos de ascitis neoplásica y cirrótica sino también en las de origen cardíaco, donde presentó valores intermedios (x ñ ES = 83.75 ñ 15.77 mg/dl). Opinamos que su incorporación rutinaria al estudio de los derrames peritoneales facilitará una rápida orientación etiológica