Protective Effects of Curcumin on Renal Oxidative Stress and Lipid Metabolism in a Rat Model of Type 2 Diabetic Nephropathy

PURPOSE: Diabetic nephropathy is a serious complication of type 2 diabetes mellitus, and delaying the development of diabetic nephropathy in patients with diabetes mellitus is very important. In this study, we investigated inflammation, oxidative stress, and lipid metabolism to assess whether curcumin ameliorates diabetic nephropathy. MATERIALS AND METHODS: Animals were divided into three groups: Long-Evans-Tokushima-Otsuka rats for normal controls, Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats for the diabetic group, and curcumin-treated (100 mg/kg/day) OLETF rats. We measured body and epididymal fat weights, and examined plasma glucose, adiponectin, and lipid profiles at 45 weeks. To confirm renal damage, we measured albumin-creatinine ratio, superoxide dismutase (SOD), and malondialdehyde (MDA) in urine samples. Glomerular basement membrane thickness and slit pore density were evaluated in the renal cortex tissue of rats. Furthermore, we conducted adenosine monophosphate-activated protein kinase (AMPK) signaling and oxidative stress-related nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling to investigate mechanisms of lipotoxicity in kidneys. RESULTS: Curcumin ameliorated albuminuria, pathophysiologic changes on the glomerulus, urinary MDA, and urinary SOD related with elevated Nrf2 signaling, as well as serum lipid-related index and ectopic lipid accumulation through activation of AMPK signaling. CONCLUSION: Collectively, these findings indicate that curcumin exerts renoprotective effects by inhibiting renal lipid accumulation and oxidative stress through AMPK and Nrf2 signaling pathway.

Reflexiones en torno a la ley N° 20.584 y sus implicancias para la investigación biomédica en Chile / Considerations on the new Chilean law about rights and duties of patients

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.

Maternal undernutrition and the offspring kidney: from fetal to adult life

Maternal dietary protein restriction during pregnancy is associated with low fetal birth weight and leads to renal morphological and physiological changes. Different mechanisms can contribute to this phenotype: exposure to fetal glucocorticoid, alterations in the components of the renin-angiotensin system, apoptosis, and DNA methylation. A low-protein diet during gestation decreases the activity of placental 11ß-hydroxysteroid dehydrogenase, exposing the fetus to glucocorticoids and resetting the hypothalamic-pituitary-adrenal axis in the offspring. The abnormal function/expression of type 1 (AT1R) or type 2 (AT2R) AngII receptors during any period of life may be the consequence or cause of renal adaptation. AT1R is up-regulated, compared with control, on the first day after birth of offspring born to low-protein diet mothers, but this protein appears to be down-regulated by 12 days of age and thereafter. In these offspring, AT2R expression differs from control at 1 day of age, but is also down-regulated thereafter, with low nephron numbers at all ages: from the fetal period, at the end of nephron formation, and during adulthood. However, during adulthood, the glomerular filtration rate is not altered, due to glomerulus and podocyte hypertrophy. Kidney tubule transporters are regulated by physiological mechanisms; Na+/K+-ATPase is inhibited by AngII and, in this model, the down-regulated AngII receptors fail to inhibit Na+/K+-ATPase, leading to increased Na+ reabsorption, contributing to the hypertensive status. We also considered the modulation of pro-apoptotic and anti-apoptotic factors during nephrogenesis, since organogenesis depends upon a tight balance between proliferation, differentiation and cell death.

Effect of D-alpha-tocopherol on tubular nephron acidification by rats with induced diabetes mellitus

The objective of the present study was to determine if treatment of diabetic rats with D-alpha-tocopherol could prevent the changes in glomerular and tubular function commonly observed in this disease. Sixty male Wistar rats divided into four groups were studied: control (C), control treated with D-alpha-tocopherol (C + T), diabetic (D), and diabetic treated with D-alpha-tocopherol (D + T). Treatment with D-alpha-tocopherol (40 mg/kg every other day, ip) was started three days after diabetes induction with streptozotocin (60 mg/kg, ip). Renal function studies and microperfusion measurements were performed 30 days after diabetes induction and the kidneys were removed for morphometric analyses. Data are reported as means ± SEM. Glomerular filtration rate increased in D rats but decreased in D + T rats (C: 6.43 ± 0.21; D: 7.74 ± 0.45; D + T: 3.86 ± 0.18 ml min-1 kg-1). Alterations of tubular acidification observed in bicarbonate absorption flux (JHCO3) and in acidification half-time (t/2) in group D were reversed in group D + T (JHCO3, C: 2.30 ± 0.10; D: 3.28 ± 0.22; D + T: 1.87 ± 0.08 nmol cm-2 s-1; t/2, C: 4.75 ± 0.20; D: 3.52 ± 0.15; D + T: 5.92 ± 0.19 s). Glomerular area was significantly increased in D, while D + T rats exhibited values similar to C, suggesting that the vitamin prevented the hypertrophic effect of hyperglycemia (C: 8334.21 ± 112.05; D: 10,217.55 ± 100.66; D + T: 8478.21 ± 119.81æm²). These results suggest that D-alpha-tocopherol is able to protect rats, at least in part, from the harmful effects of diabetes on renal function.

Efecto de diferentes grados de actividad física en la presentación de cambios anatómicos e histológicos relacionados con el envejecimiento renal / Effect of different levels of physical activity upon anatomical and histologic changes related to renal aging

Objetivos: determinar los cambios anatómicos del ejercicio en el envejecimiento renal. Metodología: estudio longitudinal experimental durante 54 semanas. Se tomaron 120 ratones machos cepa Suizo, los cuales según su actividad se dividieron en 3 grupos: sedentarios, normales y activos. El ejercicio se moduló con el espacio habitacional y el acceso al alimento. Se sacrificaron 3 animales por grupo desde la 9ª semana de edad cada 9 semanas. Se consideraron animales jóvenes aquellos menores de 27 semanas y viejos los mayores de 36. Los ratones y sus riñones se pesaron, y se estableción la relación peso riñones/peso ratón. Del riñón izquierdo de cada animal se midió la corteza y se realizó el estudio histológico con las coloraciones clásicas. Los cortes fueron analizados por 2 patólogos que no conocían el propósito del estudio; describieron cambios glomerulares y túbulo intersticiales, los cuales se clasificaron de nulos a severos. Se midieron áreas glomerulares y la relación luz/pared arterial. Resultados: El máximo crecimiento renal se observó a las 18 semanas. En la semana 54, los sedentarios tuvieron menor espesor cortical (2288,65 ± 552,75) que los normales (2502,7 ± 163,81) y los activos (2609,46 ± 273,28), con n=3 para todos los grupos. El área glomerular fue significativamente menor (P= 0,035) en sedentarios (8657,33 ± 1954,38), comparativamente con los activos (10318,64 ± 2425,14), pero entre los normales (9791,52 ± 2211,63) y los otros dos grupos no existieron diferencias significativas: n=18 para cada grupo. La atrofia tubular en animales viejos fue del 55,5 por ciento en los sedentarios, mayor que en normales y activos, en los cuales fue del 44,4 por ciento no significativo. La nefritis intersticial fue menor en normales (55,5 por ciento), en comparación con los sedentarios y activos (77,7 por ciento) no significativo. Conclusión: el grupo sedentario presentó mayor compromiso estructural en el envejecimiento renal. Aunque el ejercicio moderado puede li...

Glomerular C4d Deposition Indicates in situ Classic Complement Pathway Activation, but is not a Marker for Lupus Nephritis Activity

This study was designed to evaluate whether glomerular C4d deposition may be a useful marker of lupus nephritis activity. Twenty-one patients diagnosed as having lupus nephritis (WHO class III: 4 cases; IV: 12 cases; V: 5 cases) were included. Mean patient age was 29.3 +/- 13.5 years (range: 7-55 years). The presence and intensity of glomerular C4d deposition were compared with the corresponding histologic activity index for each case. Immunofluorescence for C4d showed diffusely granular staining along glomerular capillary loops, in all cases examined (1+, in 8 cases; 2+, in 7 cases; 3+, in 6cases). In eight cases, C4d deposition was found in the absence of capillary or mesangial C4 deposits. Moreover, the intensity of C4d deposits correlated with those of capillary IgG, IgA, C4, C1q, and fibrinogen deposits. However, C4d staining intensity did not correlate with the lupus nephritis activity index. Although glomerular capillary C4d deposition is a sensitive marker of classic complement pathway activation, it is not a sensitive marker for active lupus nephritis.

Role of VEGF in Kidney Development, Microvascular Maintenance and Pathophysiology of Renal Disease

Vascular endothelial growth factor, VEGF, is essential for endothelial cell differentiation (vasculogenesis) and for the sprouting of new capillaries from preexisting vessels (angiogenesis). In addition, there is strong evidence that VEGF is a survival factor allowing the cells to survive and proliferate under conditions of extreme stress. Hypoxia is a key regulator of VEGF gene expression. Besides hypoxia, many cytokines, hormones and growth factors can up-regulate VEGF mRNA expression in various cell types. VEGF is present in the glomerulus of both the fetal and adult kidney. The VEGF produced by glomerular epithelial cell may be responsible for maintenance of the fenestrated phenotype of glomerular epithelial cells, thus facilitating the high rate of glomerular ultrafiltration. But there is little known about the role of VEGF in the tubule. VEGF is thought to be involved in many kinds of kidney diseases. Whereas VEGF has a beneficial role in the pathogenesis in some diseases, it does harmful action in others. Because VEGF is known to be associated with the pathogenesis of some diseases, such as diabetic nephropathy, renal tumor and polycystic kidney disease, the study about the role of VEGF is going to be a target for disease control. On the other hand, an attempt at enhancing the role of VEGF has to be made at diseases like several ARF models and experimental glomerulonephritis.

Changes of glomerular basement membrane components in Vacor-induced diabetic nephropathy

OBJECTIVES: The thickening of the glomerular basement membrane in rats after Vacor ingestion was examined by electron microscopy. This study was performed to elucidate which biochemical components changed in the glomerular basement membrane after Vacor-induced diabetic glomerulopathy. METHODS: Immunohistochemical analyses of type IV collagen, laminin, fibronectin and chondroitin sulfate proteoglycan were performed. A single dose of Vacor (molecular weight 272), 80 mg/kg, was administered to adult male Wistar rats by orogastric canule, and the animals were sacrificed at 0.5, 1, 3, 7, 14, 28 and 56 days after administration. RESULTS: Mild thickening of the glomerular basement membrane was evident 7 days after Vacor administration, and the width of the glomerular basement membrane was more than twice that of normal controls at 28 and 56 days. Significantly increased expressions of type IV collagen, laminin, fibronectin and neutral polysaccharide in the thickened glomerular basement membrane were noted 14 to 56 days after administration, and a mildly increased expression of chondroitin sulfate proteoglycan appeared between 3 to 7 days. CONCLUSION: These abnormally increased glomerular basement membrane components might be part of what causes diabetic nephropathy after Vacor administration.

Structure of the Bufo arenarum kidney: renal corpuscle, neck segment and proximal tubule

The structural organization of the renal corpuscle (RC), ciliated neck segment (NS) and the proximal tubule (PT) were studied in the toad, Bufo arenarum, by means of light and transmission electron microscopy. The ciliated neck segment and the proximal tubule are located in the dorsolateral zone of the kidney, while the distal tubules are located in a ventromedial zone. RC are found between these two zones. The glomerular filter apparatus consists of the podocyte epithelium, a basement membrane, a subendothelial space and an endothelium. The podocyte emits cytoplasmatic processes extending over the surface of the glomerular capillaries. These processes divide into further processes ending in expansions known as pediceles. The basement membrane consists of a lamina rara externa and a rather thin lamina densa, while the subendothelial space contains collagen fibers and slender cytoplasmic processes of the mesangial cells. NS are composed of ciliated cells with a characteristic location of the mitochondria. The PT consists of prismatic cells with a dense luminal brush border of long microvilli and numerous apical vesicles. The basal cell membrane is increased by small infoldings. One characteristic structure of the cytoplasm is the presence of lipid droplets. The cytological structure of PT cells can be considered as an adaptation for the reabsorption of organic materials

A study of effect of guggulsterone on hyperlipidemia of secondary glomerulopathy.

Hyperlipidemia in patients of secondary glomerulopathies, a well established entity with very little knowledge of its management modifies its prognosis by predisposing these patients to develop atherosclerosis, coronary artery disease, hypertension cerebro-vascular accidents and also thromboembolic phenomenon leading to renal vein thrombosis and renal failure. Guggulsterone was administered orally in these patients in a daily divided dose of 75 mg for a period of 8 weeks together with supportive measures like high protein diet, diuretics and hematinics. Total serum lipid, total serum cholesterol, triglycerides, phospholipids, HDL, LDL, and VLDL were analysed at 4 and 8 weeks of therapy. Significant reduction was observed in the values of total serum lipid and total serum cholesterol. Other parameters of lipid profile showed downward trend except rise of HDL with insignificant difference. There was no significant side effect throughout the study.

Envejecimiento renal: conceptos actuales / Renal aging: current concepts

El proceso de envejecimiento genera una serie de cambios tanto estructurales como funcionales a nivel renal. Entre los primeros se hallan la instalación de la glomeruloesclerosis, el surgimiento de la circulación aglomerular, la membrana podocitaria y la tubulización de la capa parietal de la cápsula de Bowman, así como la formación de los divertículos tubulares. La reducción de los proteoglicanos en el parénquima renal podría vincularse con la aparición de la fibrosis intersticial y los microtrombos arteriolares que se observan en este grupo etario. Con respecto a los cambios funcionales, existe una reducción del filtrado glomerular, la tolerancia a las sobrecargas ácidas y la autorregulación de la perfusión renal, así como del Tm tubular para la glucosa y los fosfatos. Por otra parte, en los ancianos se suelen hallar alteraciones en el manejo hidroelectrolítico. El conocimiento de todos estos cambios se torna necesario para una mejor comprensión de las diferencias que las entidades nosológicas del anciano presentan respecto de las del adulto, así como para permitir una mejor y más racional terapéutica en los gerontes

Nefropatia amilóide e transplante renal

Insuficiência renal crônica secundária à amiloidose renal é rara, acometendo cerca de 0,5% dos urêmicos terminais. Säo muitas as doenças sistêmicas que podem produzir amiloidose renal. No Brasil a hanseníase é causa freqüente. Até há alguns anos tais pacientes eram recusados nos programas de diálise e transplante renal, como, em geral, todos aqueles portadores de doenças sistêmicas. Atualmente näo existem mais tais restriçöes e o sucesso de tais terapêuticas substitutivas tem sido relatado. A evoluçäo do paciente com amiloidose submetido a transplante renal é melhor do que quando mantido em diálise crônica, embora em ambos os casos seja inferior à populaçäo geral. A recidiva da amiloidose no rim transplantado é freqüente, pode ser precoce e ter evoluçäo longa. Näo foi descrita ainda perda do enxerto decorrente de recidiva. Nos pacientes portadores de hanseníase ela pode ocorrer precocemente, mesmo quando a doença esteja quiescente. A colchicina parece ser benéfica na profilaxia da recidiva em pacientes com febre familiar do Mediterrâneo. Nos demais casos seu papel ainda está para ser demonstrado. Complicaçöes infecciosas no paciente transplantado parecem ser mais freqüentes no paciente com amiloidose do que naqueles da populaçäo geral. A amiloidose sistêmica pode ser um risco adicional para o paciente. Em suma, apesar da possibilidade de recidiva, de uma possível maior predisposiçäo a infecçöes e dos riscos adicionais trazidos pela amiloidose sistêmcia, o transplante renal em portadores de amiloidose é uma modalidade terapêutica satisfatória e superior à diálise crônica. Sobrevidas superiores a dez anos têm sido descritas