Heme oxygenase 1 improves glucoses metabolism and kidney histological alterations in diabetic rats

One important concern in the treatment of diabetes is the maintenance of glycemic levels and the prevention of diabetic nephropathy. Inducible heme oxygenase 1 (HO-1) is a rate-limiting enzyme thought to have antioxidant and cytoprotective roles. the goal of the present study was to analyze the effect of HO-1 induction in chronically hyperglycemic rats. the hyperglycemic rats were divided into two groups: one group, called STZ, was given a single injection of streptozotocin; and the other group was given a single streptozotocin injection as well as daily injections of hemin, an HO-1 inducer, over 60 days (STZ + HEME). A group of normoglycemic, untreated rats was used as the control (CTL).Body weight, diuresis, serum glucose levels, microalbuminuria, creatinine clearance rate, urea levels, sodium excretion, and lipid peroxidation were analyzed. Histological alterations and immunohistochemistry for HO-1 and inducible nitric oxide synthase (iNOS) were assessed. After 60 days, the STZ group exhibited an increase in blood glucose, diuresis, urea, microalbuminuria, and sodium excretion. There was no weight gain, and there was a decrease in creatinine clearance in comparison to the CTL group. in the STZ + HEME group there was an improvement in the metabolic parameters and kidney function, a decrease in blood glucose, serum urea, and microalbuminuria, and an increase of creatinine clearance, in comparison to the STZ group.There was glomerulosclerosis, collagen deposition in the STZ rats and increase in iNOS and HO-1 expression. in the STZ + HEME group, the glomerulosclerosis and fibrosis was prevented and there was an increase in the expression of HO-1, but decrease in iNOS expression and lipid peroxidation. in conclusion, our data suggest that chronic induction of HO-1 reduces hyperglycemia, improves glucose metabolism and, at least in part, protects the renal tissue from hyperglycemic injury, possibly through the antioxidant activity of HO-1.Universidade Federal de São Paulo UNIFESP, Div Nephrol, Dept Med, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Morphol Dept, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Div Nephrol, Dept Med, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Morphol Dept, São Paulo, BrazilWeb of Scienc

Preconditioning induced by gentamicin protects against acute kidney injury: the role of prostaglandins but not nitric oxide

Nephrotoxicity is the main side effect of gentamicin (GENTA). Preconditioning (PC) refers to a situation in which an organ subjected to an injury responds less intensely when exposed to another injury. the aim of this study was to evaluate the effect of PC with GENTA on nephrotoxic acute kidney injury (AKI). GENTA group rats were injected daily with GENTA (40 mg/kg/BW) for 10 days. PC animals were injected with GENTA for 3 days (40 mg/kg/BW/daily) and, after one rest week, were injected daily with GENTA for 10 days. Animals of the L-NAME and DICLO groups were preconditioned for 3 days and then received daily injections of GENTA for 10 days; they were concomitantly treated with L-NAME (10 mg/kg/BW) and diclofenac (DICLO, 5 mg/kg/BW) for 13 days. Blood and urine were collected for measurement of serum creatinine, urea, urine sodium, protein, hydroperoxides, lipid peroxidation and nitric oxide (NO). the animals were killed; kidneys were removed for histology and immunohistochemistry for apoptosis and cell proliferation. GENTA group rats showed an increase in plasma creatinine, urea, urine sodium, hydroperoxides, lipid peroxidation, proteinuria, necrosis and apoptosis, characterizing nephrotoxic AKI. PC animals showed a decrease in these parameters and increased proliferation. the blockade of NO synthesis by L-NAME potentiated the protective effect, suggesting that NO contributed to the injury caused by GENTA. the blockade of prostaglandin synthesis with DICLO increased serum and urinary parameters, blunting the protective effect of PC. Our data suggest that PC could be a useful tool to protect against nephrotoxic AKI. (C) 2011 Elsevier Inc. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Financiadora de Estudos e Projetos (FINEP)Fundacao Oswaldo Ramos (FOR)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)UNIFESP EPM, Div Nephrol, Dept Med, BR-04023900 São Paulo, BrazilUNIFESP EPM, Div Nephrol, Dept Med, BR-04023900 São Paulo, BrazilWeb of Scienc

Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity

Necroptosis is a nonapoptotic cell death pathway. We aim to study the effect of necrostatin-1 (a specific necroptosis inhibitor) in cisplatin-induced injury. We analyzed the effect of the combined use of inhibitors of apoptosis (z-vad) and necroptosis (necrostatin-1) in acute kidney injury by cisplatin in human proximal tubule cells. Our results showed moderate effectiveness in cytoprotection after treatment with z-vad. But the concomitant use of inhibitors (z-vad and necrostatin-1) presented synergistic and additive protection. The present study analyzed the caspase-3 activity and we observed a significant decrease in the group treated with z-vad and cisplatin. However we did not observe changes in the group treated with both inhibitors (z-vad and necrostatin-1) and cisplatin. Thus, demonstrating that necroptosis is a caspase-independent mechanism. We also analyzed the effect of necrostatin-1 in vivo model. C57BL/6 mice were treated with cisplatin and/or inhibitors. The concomitant use of inhibitors (z-vad and necrostatin-1) recovered renal function and decreased levels of urinary Ngal. Additionally, we analyzed the expression of RIP-1, a specific marker for necroptosis. In animals treated with cisplatin and z-VAD levels of RIP-1 were higher. This result reinforces that necroptosis occurs only in conditions where apoptosis was blocked. However, the use of both inhibitors (z-vad and necrostatin-1) provided additional protection. In conclusion, our study has a significant potential to show in vitro and in vivo protection obtained by necrostatin-1. Therefore, our results suggest that necroptosis may be an important mechanism of cell death after kidney injury.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univiversidade Federal de Sao Paulo, Sao Paulo, BrazilUniv Fed Sao Paulo, Rua Pedro de Toledo,740,2 Andar, Sao Paulo, Brazil.FAPESP: 08/09773-4Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES).Web of Scienc

Chemical composition and larvicidal activity of the essential oils of Cordia leucomalloides and Cordia curassavica from the Northeast of Brazil

The essential oils obtained from the leaves of Cordia leucomalloides and Cordia curassavica were obtained by hydrodistillation and their chemical compositions determined by a combination of GC-MS and GC-FID. Twenty-three components were tentatively identified in both oils representing 98.6 and 91.2% of the volatile content. The oil of C. leucomalloides was characterized by a large percentage of sesquiterpenes (90.6%), being delta-cadinene (17.4%), (E)-caryophyllene (15.7%), bicyclogermacrene (12.5%) and germacrene D (11.2%) the major ones. On the other hand, the oil of C. curassavica showed similar proportions of monoterpenes (47.3%) and sesquiterpenes (43.9%) among which <FONT FACE=Symbol>a-</FONT>pinene (20.5%), beta-pinene (13.1%), (E)-caryophyllene (12.4%) and bicyclogermacrene (13.8%) were the predominant compounds. The larvicidal potential of the two oils were evaluated against the third-instar of Aedes aegypti larvae. The results showed that both oils exhibited significant activity, particularly the oil of C. leucomalloides which was able to kill 98.7% of the larvae in the concentration of 100 ppm

Heme oxygenase 1 improves glucoses metabolism and kidney histological alterations in diabetic rats

Abstract One important concern in the treatment of diabetes is the maintenance of glycemic levels and the prevention of diabetic nephropathy. Inducible heme oxygenase 1 (HO-1) is a rate-limiting enzyme thought to have antioxidant and cytoprotective roles. The goal of the present study was to analyze the effect of HO-1 induction in chronically hyperglycemic rats. The hyperglycemic rats were divided into two groups: one group, called STZ, was given a single injection of streptozotocin; and the other group was given a single streptozotocin injection as well as daily injections of hemin, an HO-1 inducer, over 60 days (STZ + HEME). A group of normoglycemic, untreated rats was used as the control (CTL). Body weight, diuresis, serum glucose levels, microalbuminuria, creatinine clearance rate, urea levels, sodium excretion, and lipid peroxidation were analyzed. Histological alterations and immunohistochemistry for HO-1 and inducible nitric oxide synthase (iNOS) were assessed. After 60 days, the STZ group exhibited an increase in blood glucose, diuresis, urea, microalbuminuria, and sodium excretion. There was no weight gain, and there was a decrease in creatinine clearance in comparison to the CTL group. In the STZ + HEME group there was an improvement in the metabolic parameters and kidney function, a decrease in blood glucose, serum urea, and microalbuminuria, and an increase of creatinine clearance, in comparison to the STZ group. There was glomerulosclerosis, collagen deposition in the STZ rats and increase in iNOS and HO-1 expression. In the STZ + HEME group, the glomerulosclerosis and fibrosis was prevented and there was an increase in the expression of HO-1, but decrease in iNOS expression and lipid peroxidation. In conclusion, our data suggest that chronic induction of HO-1 reduces hyperglycemia, improves glucose metabolism and, at least in part, protects the renal tissue from hyperglycemic injury, possibly through the antioxidant activity of HO-1.</p