1, 25-(OH)2-VitD3 attenuates renal tubulointerstitial fibrosis in diabetic kidney disease by inhibiting Snail1-SMAD3/SMAD4 complex formation / 细胞与分子免疫学杂志

Objective To investigate the effect of 1, 25-(OH)2-VitD3 (VitD3) on renal tubuleinterstitial fibrosis in diabetic kidney disease. Methods NRK-52E renal tubular epithelial cells were divided into control group (5.5 mmol/L glucose medium treatment), high glucose group (25 mmol/L glucose medium treatment) and high glucose with added VitD3 group (25 mmol/L glucose medium combined with 10-8 mmol/L VitD3). The mRNA and protein expression of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in NRK-52E cells were detected by real-time quantitative PCR and Western blot analysis respectively. The expression and localization of Snail1, SMAD3 and SMAD4 were detected by immunofluorescence cytochemical staining. The binding of Snail1 with SMAD3/SMAD4 complex to the promoter of Coxsackie-adenovirus receptor (CAR) was detected by chromatin immunoprecipitation. The interaction among Snail1, SMAD3/SMAD4 and E-cadherin were detected by luciferase assay. Small interfering RNA (siRNA) was used to inhibit the expression of Snail1 and SMAD4, and the expression of mRNA of E-cadherin was detected by real-time quantitative PCR. SD rats were randomly divided into control group, DKD group and VitD3-treated group. DKD model was established by injection of streptozotocin (STZ) in DKD group and VitD3-treated group. After DKD modeling, VitD3-treated group was given VitD3 (60 ng/kg) intragastric administration. Control group and DKD group were given normal saline intragastric administration. In the DKD group and VitD3-treated group, insulin (1-2 U/kg) was injected subcutaneously to control blood glucose for 8 weeks. The mRNA and protein levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissues were detected by real-time quantitative PCR and Western blot analysis respectively. Immunohistochemistry was used to detect the expression and localization of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissue. Results Compared with the control group, the mRNA and protein expressions of Snail1, SMAD3, SMAD4 and α-SMA in NRK-52E cells cultured with high glucose and in DKD renal tissues were up-regulated, while E-cadherin expression was down-regulated. After the intervention of VitD3, the expression levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in the DKD model improved to be close to those in the control group. Chromatin immunoprecipitation showed that Snail1 and SMAD3/SMAD4 bound to CAR promoter IV, while VitD3 prevented Snail1 and SMAD3/SMAD4 from binding to CAR promoter IV. Luciferase assay confirmed the interaction among Snail1, SMAD3/SMAD4 and E-cadherin. After the mRNA of Snail1 and SMAD4 was inhibited by siRNA, the expression of E-cadherin induced by high glucose was up-regulated. Conclusion VitD3 could inhibit the formation of Snail1-SMAD3/SMAD4 complex and alleviate the renal tubulointerstitial fibrosis in DKD.

Role of Brain Angiotensin-II in Development of Experimental Diabetic Nephropathy in Wistar Rats

Abstract The renin-angiotensin-aldosterone system (RAAS) plays a key role in diabetic nephropathy (DN). Angiotensin-II secreted during the RAAS pathway increases nephropathy. It stimulates oxidative stress which can quench nitric oxide. Reduced nitric oxide level aggravates Ang-II-induced vasoconstriction. Ang-II has also emerged as a central mediator of the glomerular hemodynamic changes that are associated with renal injury. Deletion of ACE2 is also noted due to increased Ang-II level which leads to the development of DN. We hypothesize that nephropathy caused by Ang-II in the periphery may be controlled by brain RAAS. ACE inhibitors and ARBs may show the renoprotective effect when administered through ICV without crossing the blood-brain barrier. DN was observed after 8 weeks of diabetes induction through alloxan. Administration of captopril and valsartan once and in combined therapy for 2 weeks, significantly reduced urine output, blood urea nitrogen, total protein in the urine, serum cholesterol, serum creatinine, serum triglycerides, and kidney/body weight ratio as compared to diabetic control rats. Further, combination therapy significantly increased the body weight and serum nitrate level as compared to diabetic control animals. However, increased ACE2 levels in the brain may reduce the sympathetic outflow and might have decreased the peripheral activity of Ang-II which shows beneficial effects in DN.

Preventive role of gum Arabic administration on STZ induced diabetic kidney disease in rats; renal antioxidant and histopathological evidence / Función preventiva de la administración de goma arábiga en la enfermedad renal diabética inducida por STZ en ratas; antioxidante renal y evidencia histopatológica

This study was set to investigate the effect of gum Arabic (G.A.) on diabetic kidney disease. We divided sixty male Sprague rats randomly into six groups. Normal control, normal rats treated with G.A., untreated diabetic rats, diabetic rats treated with insulin, diabetic rats treated with G.A., and diabetic rats treated with both insulin and G.A. Diabetes was induced by a single intraperitoneal injection of STZ. Forty eight hr post injections. Insulin was injected subcutaneously (1.6/IU/100g/day). We provided G.A. in drinking water (10 %w/ v).). At the end of the twelve weeks, blood was drawn for measurement of blood glucose, glycosylated hemoglobin (HbA1C), serum lipids, serum creatinine, and blood urea. Renal tissue oxidative stress (O.S.) was assessed by measuring the activities of superoxide dismutase (SOD) and catalase (CAT), and the concentrations of reduced glutathione (GSH) and malondialdehyde (MDA). For histological assessments, sections from segments of kidneys were processed and stained with hematoxylin and eosin (H&E) for assessment under the light microscope. STZinduced diabetes caused an elevation of blood glucose, HbA1c, urea and creatinine, triglycerides LDL and cholesterol, MDA with reduction of HDL, GSH level, and CAT and SOD activities. Histologically, kidneys from diabetic rats showed marked glomerular and tubular changes. Administration of G.A. alone to diabetic rats had a significant hypoglycemic, hypolipidemic, and antioxidant effect, although the levels achieved remained significantly abnormal compared with the untreated group with no effect on urea and creatinine levels. Co-administration of G.A. with insulin reversed the impact of D.M. on all parameters evaluated including the histological changes and led to normal urea and creatinine levels. We concluded that G.A., in combination with insulin, improves chemically-induced diabetes and its renal complications, possibly by modulation of oxidative stress.

En este estudio se evaluó el efecto de la goma arábiga (GA) en la enfermedad renal diabética. Dividimos sesenta ratas macho Sprague Dawley al azar en seis grupos. Control normal, ratas normales tratadas con GA, ratas diabéticas no tratadas, ratas diabéticas tratadas con insulina, ratas diabéticas tratadas con GA y ratas diabéticas tratadas con insulina y GA. La diabetes fue inducida por una sola inyección intraperitoneal de STZ. Cuarenta y ocho horas después se inyectó insulina por vía subcutánea (1,6 / UI / 100 g / día). A los animales se les dió GA en agua potable (10 % p / v)). Al final de las doce semanas, se extrajo sangre para medir la glucosa, la hemoglobina glicosilada (HbA1C), los lípidos en suero, la creatinina en suero y la urea en sangre. El estrés oxidativo del tejido renal (SO) se evaluó midiendo las actividades de la enzima superóxido dismutasa (SOD) y la catalasa (CAT), y las concentraciones de glutatión reducido (GSH) y malondialdehído (MDA). Para las evaluaciones histológicas, se procesaron secciones de segmentos de riñones y se tiñeron con hematoxilina y eosina (H & E) para análisis bajo microscopio óptico. La diabetes inducida por STZ causó una elevación de la glucosa en sangre, HbA1c, urea y creatinina, triglicéridos LDL y colesterol, MDA con reducción de las actividades de HDL, GSH y CAT y SOD. Histológicamente, los riñones de ratas diabéticas mostraron marcados cambios glomerulares y tubulares. La administración de GA solo en las ratas diabéticas tuvo un efecto hipoglucémico, hipolipidémico y antioxidante significativo, aunque los niveles alcanzados permanecieron significativamente anormales en comparación con el grupo no tratado, sin ningún efecto sobre los niveles de urea y creatinina. La dministración conjunta de GA con insulina revirtió el impacto de DM en todos los parámetros evaluados, incluidos los cambios histológicos y condujeron a niveles normales de urea y creatinina. Concluimos que GA en combinación con insulina, mejora la diabetes inducida químicamente y sus complicaciones renales, posiblemente mediante la modulación del estrés oxidativo.

MicroRNAs: new biomarkers and promising therapeutic targets for diabetic kidney disease / MicroRNAs: novos biomarcadores e alvos terapêuticos promissores da doença renal do diabetes

Abstract Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus associated with significant morbidity and mortality regarded as a global health issue. MicroRNAs - small RNA molecules responsible for the post-transcriptional regulation of gene expression by degradation of messenger RNA or translational repression of protein synthesis - rank among the factors linked to the development and progression of DKD. This study aimed to offer a narrative review on investigations around the use of microRNAs in the diagnosis, monitoring, and treatment of DKD. Various microRNAs are involved in the pathogenesis of DKD, while others have a role in nephroprotection and thus serve as promising therapeutic targets for DKD. Serum and urine microRNAs levels have also been considered in the early diagnosis and monitoring of individuals with DKD, since increases in albuminuria, decreases in the glomerular filtration rate, and progression of DKD have been linked to changes in the levels of some microRNAs.

Resumo A doença renal do diabetes (DRD) é uma complicação crônica do diabetes mellitus associada à elevada morbidade e mortalidade, considerada um problema de saúde mundial. Dentre os fatores associados ao desenvolvimento e à progressão da DRD, destacam-se os microRNAs, que consistem em pequenas moléculas de RNA que regulam a expressão gênica por meio da degradação pós-transcricional do RNA mensageiro ou inibição translacional da síntese proteica. Este estudo teve como objetivo realizar uma revisão narrativa buscando investigar os microRNAs como auxiliares no diagnóstico, monitoramento e tratamento da DRD. Vários microRNAs estão envolvidos na patogênese da DRD, enquanto que outros têm papel nefroprotetor, consistindo assim em alvos terapêuticos promissores para o tratamento da DRD. A dosagem laboratorial dos microRNAs no soro e na urina também é muito promissora para o diagnóstico precoce e o monitoramento da DRD, já que os níveis de alguns microRNAs se alteram antes do aumento da albuminúria e da diminuição da taxa de filtração glomerular e podem ainda se alterar com a progressão da DRD.

Macrophage migration inhibitory factor antagonist (p425) ameliorates kidney histopathological and functional changes in diabetic rats / Antagonista (p425) do fator de inibição da migração de macrófagos (MIF) melhora as alterações histopatológicas e funcionais renais em ratos diabéticos

Abstract Introduction: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. Methods: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. Results: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. Conclusion: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.

Resumo Introdução: Supõe-se que elevações da expressão do fator de inibição da migração de macrófagos (MIF) possam contribuir para a patogênese da nefropatia diabética (ND). O objetivo do presente estudo foi investigar os efeitos renais da inibição do MIF em um modelo experimental diabético. Métodos: Dezoito ratos Wistar machos (230 ± 20g) foram divididos em três grupos: 1) controle, 2) diabético (STZ 50 mg/kg dissolvida em soro fisiológico, IP), 3) diabético + antagonista do MIF (p425 1 mg/kg por dia IP no 21o dia por 21 dias consecutivos). O tratamento começou após a identificação de aumento significativo na albuminúria nos ratos diabéticos em relação aos controles. Os ratos foram mantidos individualmente em gaiolas metabólicas (8h-14h) e amostras de urina foram colhidas no 21o e no 42o dia. Ao final do estudo, amostras de sangue e tecido foram colhidas para análises bioquímicas (BS, excreção urinária de proteína, excreção urinária de GAGs, BUN, Cr, Na e K) e histológicas. Resultados: O presente estudo demonstrou que o antagonista do MIF (p425) diminuiu significativamente proteinúria, excreção urinária de GAGs , relação proteína/creatinina na urina, BUN e Cr no grupo com ND induzida por estreptozotocina. As alterações patológicas foram significativamente abrandadas nos ratos com ND que receberam antagonista do MIF (p425). Conclusão: Coletivamente, os dados sugerem que o antagonista do MIF (p425) teve efeito protetor contra lesões funcionais e histopatológicas da ND.

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

ABSTRACT Objective The objective of this study was to evaluate the role of oxidative stress in an experimental model of streptozotocin-induced diabetic nephropathy in rats. Materials and methods Wistar, adult, male rats were used in the study. Animals were divided in the following groups: Citrate (control, citrate buffer 0.01M, pH 4.2 was administrated intravenously - i.v - in the caudal vein), Uninephrectomy+Citrate (left uninephrectomy-20 days before the study), DM (streptozotocin, 65 mg/kg, i.v, on the 20th day of the study), Uninephrectomy+DM. Physiological parameters (water and food intake, body weight, blood glucose, kidney weight, and relative kidney weight); renal function (creatinine clearance), urine albumin (immunodiffusion method); oxidative metabolites (urinary peroxides, thiobarbituric acid reactive substances, and thiols in renal tissue), and kidney histology were evaluated. Results Polyphagia, polydipsia, hyperglycemia, and reduced body weight were observed in diabetic rats. Renal function was reduced in diabetic groups (creatinine clearance, p < 0.05). Uninephrectomy potentiated urine albumin and increased kidney weight and relative kidney weight in diabetic animals (p < 0.05). Urinary peroxides and thiobarbituric acid reactive substances were increased, and the reduction in thiol levels demonstrated endogenous substrate consumption in diabetic groups (p < 0.05). The histological analysis revealed moderate lesions of diabetic nephropathy. Conclusion This study confirms lipid peroxidation and intense consumption of the antioxidant defense system in diabetic rats. The association of hyperglycemia and uninephrectomy resulted in additional renal injury, demonstrating that the model is adequate for the study of diabetic nephropathy.

Endoplasmic reticulum stress and renal lesion in mice with combination of high-fat diet and streptozotocin-induced diabetes

ABSTRACT PURPOSE : To investigate in the kidney the pathologic changes and expression of GRP78 and CHOP in the Kunming (KM) mice with combination of high-fat diet and streptozotocin-induced diabetes. METHODS : Sixty two male KM mice were randomly divided into a normal control (NC) group (n=20) and a high-fat diet (HFD) group (n=42). After a four-week dietary manipulation, the KM mice in the HFD group were injected intraperitoneally with streptozotocin to induce diabetes. After diabetic models were successfully established, the kidneys were excised and conserved for further test. RESULTS : No significant difference in the body weight was observed after the dietary manipulation (p=0.554). After the streptozotocin was injected, fasting blood glucose levels in the diabetes group (DM) were significantly higher than that in the NC group (p＜0.0001). Glomerular atrophy observed under light microscope in the DM group was more serious compared with the NC group. The expression of GRP78 and CHOP in the kidneys of the mice in the DM group were higher compared with the NC group. CONCLUSION : Renal lesion occurs in the diabetic Kunming mice induced by combination of high-fat diet and low-dose streptozotocin, and endoplasmic reticulum stress and CHOP may contribute to the injury process.

Enfermedad renal por depósito idiopático de cadenas livianas: Caso clínico / Kidney involvement in idiopathic light chain disease: Report of one case

Idiopathic Light Chain disease (ILCD) is a systemic disease characterized by a deposit in different organs of light chain monoclonal immunoglobulins, produced by an abnormal clone ofB cells. It is usually found in the course ofa plasma cell dyscrasia and in other lymphoproliferative alterations; however it may occur in absence of any hematologic disease and is denominated as idiopathic. We report a 51-year-old mole admitted to the hospital due to anasarca. Laboratory evaluation showed a serum creatinine of 1.4 mg/dl, a serum albumin of1.6 g/dl, a serum cholesterol of 687 mg/dl and a proteinuria of 5.3 g/day Light chains with a predominance of a monoclonal component were identified in urinary proteins by electrophoresis and kappa chains were identified by immunofixation. A renal biopsy showed a diffuse nodular glomerulopathy with a 35% tubular atrophy and interstitial sclerosis. Electrón microscopy confirmed light chain deposition. The bone marrow biopsy showed a myeloid hyperplasia. Thepatient was initially treated with methylprednisolone and plasmapheresis with a reduction in serum creatinine and disappearance of urinary kappa component. Albuminuriapersisted and a malnutrition-inflammatory complex syndrome was diagnosed. Hemodialysis with ultrafiltration was started along with cyclophosphamide. Thepatient receivedhemodialysisforsixmonths and continued with methylprednisolone.

Neuroprotective effect of melatonin in a rat model of streptozotocin-induced diabetic neuropathy: Light and electron microscopic study

Diabetes mellitus [DM] is the most common cause of peripheral neuropathy in most countries. Oxidative stress appears to be the most important pathogenic factor in underlying diabetic complications, including neuropathy. The present study aimed to investigate the possible neuroprotective effects of melatonin [MLT] in a rat model of streptozotocin [STZ]-induced diabetic neuropathy. Thirty-six [15 weeks old] adult male albino rats were divided into three groups. Group I [n=6] served as the control group. In group II [n=15], DM was induced by a single intraperitoneal injection of STZ at a dose of 60 mg/kg body weight and rats were sacrificed after 6 weeks. Rats in group III [n=15] were rendered diabetic by a single intraperitoneal injection of STZ, and immediately after confirmation of DM, that is, 48 h after STZ [random blood sugar > 200 mg/dl], rats received MLT at a dose of 10 mg/kg/day by intraperitoneal injection for 6 weeks. Body weight and random blood sugar were measured for all groups. Sciatic nerves of all the sacrificed animals were subjected to light microscopic, electron microscopic, and morphometric studies. In group II, DM induction was associated with the occurrence of neuropathy manifested by marked thickening of the epineurium and perineurium. Nerve fibers exhibited marked axonal atrophy, axonal shrinkage, axon-myelin separation, and in some sections total axonal destruction. Severe demyelination with evidence of myelin destruction was observed in the form of splitting and decompaction of myelin sheath lamellae, as well as vacuolization of the myelin sheath, forming fermentation chambers. In the MLT-treated group, vacuolization of the myelin sheath decreased remarkably and mild local axon separation from myelin sheaths was detected. Morphometric analysis revealed a significant increase in the number of total and apparently normal fibers and decrease in the number of apparently degenerated fibers in the nerve sections of MLT-treated rats, compared with nontreated diabetic rats. This study showed that MLT, in early stages of DM induction, decreased the destructive progress of DM and provided neuroprotection against damage resulting from STZ-induced hyperglycemia. Thus, it is recommended to start MLT therapy as soon as diagnosis of DM is established and even earlier in individuals at high risk for developing DM

Relationship between the Morphology of Diabetic Macular Edema and Renal Dysfunction in Diabetes

PURPOSE: To determine the correlation between renal dysfunction and the morphologic changes of macular edema in diabetes. METHODS: The current study included 93 patients with diabetic macular edema based on optical coherence tomography (OCT) who completed systemic condition testing one month before or after the OCT. Based on the OCT findings, patients were divided into the following five groups: group A (diffuse), group B (cystoid), group C (serous), group D (vitreomacular tractional), and group E (a mixed presence of cystoid and serous types). In each group, we performed a retrospective analysis of serum albumin, urine albumin, and serum creatinine. We also analyzed the patients in whom serum albumin was 1.6 mg/dL. Urine albumin was measured in all five groups. In each group, a comparative analysis was performed using Fisher's exact test. RESULTS: The number of patients who were assigned to groups A to E was 15, 46, 6, 3, and 23, respectively. According to a comparison of the patients in whom the serum albumin and serum creatinine were abnormal, there was no significant difference among the five groups. The proportion of patients in whom the urine albumin was abnormal was significantly greater in group C (67%) than in groups A (7%), B (20%), or E (22%). CONCLUSIONS: Serous-type macular edema occurred more frequently than other types of macular edema in patients with albuminuria.

Relationship between the Morphology of Diabetic Macular Edema and Renal Dysfunction in Diabetes

PURPOSE: To determine the correlation between renal dysfunction and the morphologic changes of macular edema in diabetes. METHODS: The current study included 93 patients with diabetic macular edema based on optical coherence tomography (OCT) who completed systemic condition testing one month before or after the OCT. Based on the OCT findings, patients were divided into the following five groups: group A (diffuse), group B (cystoid), group C (serous), group D (vitreomacular tractional), and group E (a mixed presence of cystoid and serous types). In each group, we performed a retrospective analysis of serum albumin, urine albumin, and serum creatinine. We also analyzed the patients in whom serum albumin was 1.6 mg/dL. Urine albumin was measured in all five groups. In each group, a comparative analysis was performed using Fisher's exact test. RESULTS: The number of patients who were assigned to groups A to E was 15, 46, 6, 3, and 23, respectively. According to a comparison of the patients in whom the serum albumin and serum creatinine were abnormal, there was no significant difference among the five groups. The proportion of patients in whom the urine albumin was abnormal was significantly greater in group C (67%) than in groups A (7%), B (20%), or E (22%). CONCLUSIONS: Serous-type macular edema occurred more frequently than other types of macular edema in patients with albuminuria.

Efecto de la administración de espironolactona sobre la pérdida de podocitos y la progresión de la nefropatía diabética experimental / Effects of spironolactone administration on the podocytes loss and progression of experimental diabetic nephropathy

Objetivos. Evaluar el efecto de espironolactona (SPL) sobre la pérdida de los podocitos durante la progresión de la nefropatía diabética (ND) experimental. Materiales y métodos. Aleatoriamente un grupo de ratas macho Holtzman recibieron estreptozotocina (grupo diabético) o citrato buffer (grupo control). Las ratas diabéticas fueron tratadas con SPL (50 mg/kg/día). El área glomerular y la celularidad fueron evaluadas por métodos histomorfométricos. La lesión y pérdida de podocitos fue evaluada por la expresión de desmina y Wt-1, respectivamente. La expresión génica del TGF-β1 se evaluó mediante RT-PCR. Resultados. Los niveles de glucosa, el área glomerular, la expansión mesangial y el contenido de colágeno se incrementaron significativamente en las ratas diabéticas. La administración de SPL previno estos cambios sin modificar los niveles de glucosa. La inmunotinción para Wt-1 se redujo significativamente, mientras que la inmunotinción para desmina se incrementó drásticamente en las ratas diabéticas. El tratamiento con SPL previno el incremento de expresión de desmina y la pérdida de expresión de Wt-1. Asimismo, la administración de SPL previno el incremento de la expresión del mRNA del TGF-β1 en las ratas diabéticas. Conclusiones. El tratamiento con SPL, a través de efectos glucosa independientes, atenúa la perdida de podocitos y la progresión de los cambios morfológicos de la ND. Los presentes resultados sugieren que estos efectos son mediados, al menos en parte, por la inhibición de la la expresión del mRNA del TGF-β1.

Objectives. Evaluate the effect of spironolactone (SPL) on the loss of podocytes during the progression of experimental diabetic nephropathy (DN). Materials and methods. A group of male Holtzman rats randomly received streptozotocin (diabetic group) or a buffer citrate (control group). Diabetic rats were treated with SPL (50 mg/kg/day). The glomerular area and the cellularity were evaluated by histomorphometric methods. The injury and loss of podocytes was assessed by desmin expression and Wt-1, respectively. The gene expression of TGF-β1 was assessed by RT-PCR. Results. Glucose levels, the glomerular area, the mesangial expansion and collagen content increased significantly in diabetic rats. The administration of SPL prevented these changes without changing glucose levels. Immunostain for Wt-1 decreased significantly while immunostain for desmin increased dramatically in diabetic rats. Treatment with SPL prevented the increase of desmin expression and the loss of Wt-1 expression. Furthermore, the administration of SPL prevented the increase of TGF-β1 mRNA expression in diabetic rats. Conclusions. Treatment with SPL, through independent glucose effects, reduces the loss of podocytes and the progression of DN morphological changes. These results suggest that these effects are mediated, at least in part, by the inhibition of TGF-β1 mRNA expression.

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN), a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular filtration rate and the loss of glomerular podocytes, tubulointerstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational effort to control the disease, a significant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs). The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.

Proteinuria in cystic fibrosis: a possible correlation between genotype and renal phenotype / Proteinúria na fibrose cística: possível correlação entre genótipo e fenótipo renal

Objective: To assess proteinuria in patients with cystic fibrosis (CF), and to correlate proteinuria with genotype, CF-related diabetes and disease severity. Methods: A prospective study was carried out over a six-month period and involving 22 CF patients. After the collection and analysis of 24-h urine samples, the patients were divided into two subgroups: protein excretion < 150 mg/day (low-proteinuria); and protein excretion ≥ 150 mg/day (highproteinuria). Patient charts were reviewed to obtain data on genotype and CF-related diabetes. Disease severity was assessed based on acute exacerbations in the last six months and FEV1 measured during the study period. To assess the correlation between genotype and proteinuria, the two main mutations (ΔF508 and R334W) were evaluated. Due to the existence of genotype ΔF508/R334W, two categories were created to enable statistical analysis, ΔF508 being evaluated in category 1 and R334W being evaluated in category 2. Results: The ΔF508 mutation tended to be associated with normal protein excretion: 100% of the low-proteinuria subgroup patients were consideredΔF508 in category 1, compared with 86.7% in category 2. Protein excretion tended to be higher in patients withthe R334W mutation: 60.0% of the high-proteinuria subgroup patients were considered R334W in category 1, compared with 80.0% in category 2 (p = 0.009 and p = 0.014, respectively). No significant association was foundfor any of the other variables. Conclusions: The results suggest that genotype is associated with renal phenotype, depending on the mechanism by which the genotype alters the function of the cystic fibrosis transmembrane conductance regulator gene.

Objetivo: Avaliar a proteinúria em pacientes com fibrose cística (FC) e correlacioná-la com o genótipo, com adiabetes relacionada à FC e com a gravidade da doença. Métodos: Estudo prospectivo realizado num período deseis meses com 22 pacientes com FC. Efetuada proteinúria de 24 h com a divisão dos pacientes em dois subgrupos:proteinúria < 150 mg/dia (proteinúria-baixa); e proteinúria ≥ 150 mg/dia (proteinúria-alta). Revisamos os prontuários clínicos para a coleta de informações sobre o genótipo e a presença de diabetes relacionada à FC. A gravidade da doença foi avaliada pelas exacerbações agudas no último semestre e pelo VEF1 durante o período de estudo. Para avaliar a correlação entre genótipo e proteinúria, consideraram-se as duas principais mutações, ΔF508 e R334W. Dada a existência do genótipo ΔF508/R334W, foram criadas duas categorias para se proceder à avaliação estatística, sendo esse genótipo considerado ΔF508 na categoria 1 e R334W na categoria 2. Resultados: A mutação ΔF508 se associou com valores normais de proteinúria: 100% dos pacientes do subgrupo proteinúria-baixa foram considerados ΔF508 na categoria 1, comparados a 86,7% na categoria 2. Em pacientes com a mutação R334W, osvalores de proteinuria foram mais elevados: 60,0% dos pacientes do subgrupo proteinúria-alta foram considerados R334W na categoria 1, comparados a 80,0% na categoria 2 (p = 0,009 e p = 0,014, respectivamente). Para as outras variáveis, não houve associação significativa. Conclusões: Os resultados sugerem que há uma associação entre o genótipo e o fenótipo renal, dependendo do mecanismo pelo qual o genótipo altera a função do generegulador de condutância transmembrana da fibrose cística.

Papel da ingestão de soja na nefropatia diabética / Role of soy intake in diabetic nephropathy

O papel específico das modificações da dieta no tratamento da nefropatia diabética (ND) ainda não está elucidado. A substituição de proteína de origem animal por soja em pacientes com Diabete Melito (DM) poderia ser benéfica para a função renal. O objetivo do presente manuscrito foi revisar criticamente as evidências acerca do papel da soja na ND. Foram selecionados seis ensaios clínicos randomizados conduzidos em pacientes com DM, dentre os quais cinco demonstraram melhora de pelo menos um marcador de função renal com a dieta com soja. Os mecanismos através dos quais essas dietas promoveriam melhora da ND não foram elucidados, assim como não está estabelecido ainda se há distinção no efeito benéfico aos rins dos diferentes produtos à base de soja disponíveis no mercado. Novos estudos são necessários para que tais questões possam ser elucidadas e para que os benefícios da soja na ND possam ser confirmados.

The specific role of dietary changes in the treatment of diabetic nephropathy (DN) has not yet been elucidated. The animal source protein replacement for soy in patients with Diabetes Mellitus (DM) may provide potential benefits for renal function. The aim of the present manuscript was to perform a critical review of evidence about the role of soy in DN. Six randomized clinical trials conducted in patients with DM were selected, and five of them showed improvement of at least one marker of renal function with the soy diet. However, the mechanisms by which these diets promote improvement in DN have not been elucidated. It is not yet known whether there are distinguishable renal benefits ensured by different soy-based products available on the market. Further studies are needed to clarify theses aspects and to confirm the benefits of soy in DN.

Stereological evaluation of renal glomeruli in offspring of diabetic female rats

Although in vitro studies have shown that high concentrations of glucose can induce dysmorphogenesis of the embryonic kidney, the possible adverse effects of exposure to intrauterine hyperglycemia on kidney development, especially in regard to nephrogenesis, has not been evaluated. The aim of this study is to investigate the effects of maternal diabetes on glomeruli structures of the offspring, focusing on the following parameters: glomeruli volume and number, mesangium volume, mesangial cell number and glomerular capillary volume. Before mating, fifteen female Sprague Dawley rats, divided into three groups, were diabetes induced by a single intraperitoneal dose of 65 mg/ kg streptozotocyn [STZ]. After 30 days of breast feeding, ten offsprings from each group [two per mother] were randomly selected for kidney removal. The kidneys were weighed and their tissues were processed for light microscopy. Glomerular features were evaluated quantitatively using dissection as well as the Cavalieri method and were then compared with sham and control groups. At birth, the mean body weight of diabetic mothers' offspring [DO] was significantly lower than that of the control group's offspring [CO] and sham group's offspring [SO] [p=0.001], however, the mean body weight of the 30 day-old DO was not lower than that of CO and SO [p > 0.05]. The total renal volumes, cortical volumes, glomerular mean and total volumes, total mesangeal volumes, total capillary volumes and total glomerular numbers were significantly lower in the DO than in CO and SO [p < 0.05]. The numerical density of glomeruli and mesangial cells per glomeruli were significantly greater in DO than in CO and SO [p < 0.05]. We concluded that intrauterine hyperglycemia is accompanied by a nephron deficit which may not be compensated within the first 30 days after birth

Niveles de hemoglobina glicosilada como predictor de control metabólico: en diabéticos que acudieron al Hospital "Dr. Patrocinio Peñuela Ruíz" y consulta privada San Cristóbal, estado Táchira: marzo-mayo 2007 / Hemoglobin glycosylated levels as a predictor of metabolic control: in diabetics attending the Hospital Dr. Patrocinio Peñuela Ruíz and private consultation San Cristobal, state Táchira: march-may 2007

Se determinaron niveles de hemoglobina glicosilada (HbA1c) como parámetro de control metabólico en diabéticos hospitalizados o en consulta en el Hospital del Seguro Social y medio privado, como parte de estudio multicentrico de OMS para conocer este parámetro en los venezolanos. Se analizó el número de diabéticos atendidos, los niveles de HbA1c, sexo, tipo de tratamiento e índice de masa corporal (IMC). Se atendieron 124 diabeticos, 48 hombres (38,70 por ciento) y 76 mujeres (61,29 por ciento), 7 eran diabéticos tipo 1 y 117 diabéticos tipo 2, encontrándose niveles promedio HbA1c 8,5 por ciento, IMC 29,7. Se concluye que el análisis de HbA1c permite evaluar el control metabólico de los pacientes diabéticos, evidenciándose mal control en el grupo estudiado. Se hace necesario ajustes en estrategias de control en estos pacientes.

Nefropatia Diabética nas Unidades de Diálise da Região Sul de Santa Catarina: perfil clínico-epidemiológico / Diabetic Nephropaty in Dialisis Units of South Santa Catarina State: clinic-epidemiological outline

Objetivos: Conhecer a prevalência de Nefropatia Diabética (ND) nas Unidades de Diálise (UD) na Região Sul de Santa Catarina e o perfil clínico-epidemiológico dos pacientes. Método: Estudo descritivo, observacional, retrospectivo, transversal, quantitativo, dos pacientes com nefropatia diabética, em tratamento dialítico, de julho de 2003 a julho de 2005 nas Unidades de Diálise de Araranguá, Criciúma e Tubarão.Resultados: Dos 211 pacientes, 86 (40,75%) tinham o diagnóstico de ND. O Diabetes Melito tipo 2 (DM 2) foi o mais prevalente com 89,5% dos pacientes. O sexo masculino correspondeu a 52% dos casos, e o feminino a 48%. Em 69 pacientes a história familiar para DM 2 foi positiva. Quarenta e um fumavam e 45 não fumavam. Sessenta e sete pacientes (78%) eram brancos, 6 (7%) negros, 13 (15%) pardos. A média de idade dos pacientes em foi de 58,27 anos. A média de tempo entre o diagnóstico e início do tratamento foi de 13,6 anos. A Hipertensão Arterial Sistêmica ocorreu associada ao DM 2 em 71% dos pacientes, a Neuropatia Periférica em22%, a Retinopatia Diabética e a Doença Cardiovascular em 24,4% e o Acidente Vascular Cerebral em 11,6%. Conclusão: A ND gera grande morbidade,mortalidade e altos custos quando está em um estágio que necessita de diálise. Medidas preventivas são úteis para evitar que os fatores de risco estabeleçam um quadro de ND.

Objectives: To know the prevalence of Diabethic Nefropaty in Dialisis Units of Southern Santa Catarina State and the pacients clinic-epidemiological outline. Methods: Descritive, observacional, retrospective, transversal, qualitative study, of Diabethic Nefropaty pacients, in dialitic treatment, beetwen July 2003 and July 2005 in Dialisis Units of Araranguá, Criciúma and Tubarão.Results: There were 211 pacients, and 86 (40,75%) with Diabethic Nefropaty. The Diabetes Melito type 2 (DM 2) was the most prevalent (89,5% of pacients).The male sex was present in 52%, and the female in 48% . In 69 pacients the familiar history to DM 2 was present. . Forty-one pacients smoking and forty-five doesn't smoking. Sixty seven pacients (78%) were whites, 6 (7%) blacks, 13 (15%) mixed. The mean agewas 58,27. The time between diagnostic and treatment started was 13,6 years. Hypertension was present with DM 2 in 71% pacients, Periferic Neuropaty in 22%, Diabethic Retinopaty and Cardiovascular disease in 24,4% , and the Stroke in 11,6%. Conclusion: Diabethic Nefropaty causes highmorbidity, mortality and high costs when is in the stage that needs of dialisis. Preventive measures are avaliableto impede that risc factors lead to ND.

Reduction of podocytes number in late diabetic alloxan nephropathy: prevention by glycemic control

PURPOSE: To determine podocyte number and GBM thickness in diabetic rats either under glycemic control or without glycemic control at 6 and 12 months after diabetes induction. METHODS: 100 wistar rats weighing 200-300g were divided into 6 groups: Normal group (N6 and N12- 25 rats); Diabetic group (D6 and D12- 25 rats), diabetic treated group ( DT 6 and DT 12- 25 rats) on insulin 1,8- 3,0 IU/Kg associated with acarbose (50mg to 100g of food) daily mixed in chow. Alloxan was injected intravenously in a dose of 42 mg/Kg of weight. Body weight, waterintake, 24-h diuresis, glycemia and glucosuria were determined before induction, 7 and 14 days after induction and monthly thereafter. Treatment started at day 14. Three groups were sacrificed at 6 months (N6,D6, DT6) and 3 groups at 12 months (N12, D12, DT12) with the renal tissue being prepared for electron microscopy. RESULTS: Glycemia in DT6¨and in DT12 was significantly different from that in D6 and D12 rats and similar to that in N6 and N12 animals. The number of podocytes in DT6 was not different from that in N6 and D6 (median = 11); the number of podocytes in DT12 (median = 11) differed from that in D12 (median = 8), but not from that in N12 (median = 11). GBM thickness in D6 (0.18 micrometers) was lower than in D12 (0.29 micrometers); while in DT6 (0.16 micrometers) it was lower than in D6 (0.18 micrometers). In DT12 (0.26 micrometers), it was lower than in D12 (0.29 micrometers). CONCLUSION: The control of hyperglycemia prevented GBM thickening in early and late (12 mo) alloxan diabetic nephropathy and podocyte number reduction.

OBJETIVO: Avaliar o número de podócitos e espessamento da membrana basal glomerular (MBG) em ratos diabéticos com e sem controle glicêmico com 6 e 12 meses da indução. MÉTODOS: 100 ratos Wistar com 200-300g compuseram 6 grupos: Normal (N6, N12 - 25 animais) Diabético (D6,D12 - 25 animais) e diabético tratado com insulina 1,8 a 3,0 U/Kg e acarbose misturada a ração (50g para cada 100g de ração) (DT6 e DT12 - 25 animais). Aloxana foi ministrada via endovenosa na dose de 42mg/Kg. Peso, ingestão hídrica e diurese de 24 horas e glicemia e glicosúria foram determinados antes da inoculação, 7 e 14 dias após e mensalmente. No 14ª dia foi iniciado o tratamento. Três grupos de animais (N6, D6 e DT6) foram sacrificados no 6° mês e três grupos (N12, D12 e DT12), no 12ª mês sendo o tecido renal processado para estudo à microscopia eletrônica. RESULTADOS: A glicemia dos animais DT6 e DT12 diferiram significativamente, dos ratos D6 e D12, e não diferiram dos grupos N6 e N12. O número de podócitos do grupo DT6 não diferiu de N6 e D6 (mediana=11); o número de podócitos de DT12 (mediana=11) diferiu de D12 (mediana=8) e não diferiu de N12 (mediana=11). O espessamento da MBG de D6 (0,18 micrômetros) foi menor que D12 (0,29 micrômetros); de DT6 (0,16 micrômetros) foi menor que D6 (0,18 micrômetros) e de DT12 (0,26 micrômetros) foi menor que D12 (0,29 micrômetros). CONCLUSÃO: O controle da hiperglicemia preveniu o espessamento da MBG na nefropatia diabética aloxânica precoce (6 meses) e tardia (12 meses), e a diminuição do número de podócitos.

The combination of thrombotic microangiopathy and nodular sclerosis in light chain deposition disease.

The authors reported the first case of nodular glomerulosclerosis, mesangiolysis, and thrombotic microangiopathy in a 69-year-old Thai man with chronic glomerulopathy from light chain deposition disease associated with multiple myeloma and kappa monoclonal gammopathy. He presented with subacute onset of generalized edema, hypertension, and renal insufficiency. Blood examinations revealed kappa monoclonal gammopathy. The diagnosis of multiple myeloma was confirmed by bone marrow aspiration and biopsy. The renal pathologies demonstrated specific findings for light chain deposition disease which were type II nodular glomerulosclerosis, strongly PAS-stained tubular basement membrane, monotypic-kappa light chain deposition along tubular and glomerular basement membranes, and granular electron dense deposits in electron microscopy. However the authors also found the concomitant findings of mesangial and endothelial injuries which were mesangiolysis and thrombotic microangiopathy. Of interest, type II nodular sclerosis and thrombotic microangiopathy were caused by the same cell injury. These might shed new light on the pathogenesis of glomerular injury in monoclonal immunoglobulin deposition disease (MIDD).