RESUMEN
Metabolic syndrome (MS) is the association of three or more pathologies among which obesity, hypertension, insulin resistance, dyslipidemia, and diabetes are included. It causes oxidative stress (OS) and renal dysfunction. Hibiscus sabdariffa L. (HSL) is a source of natural antioxidants that may control the renal damage caused by the MS. The objective of this work was to evaluate the effect of a 2% HSL infusion on renal function in a MS rat model induced by the administration of 30% sucrose in drinking water. 24 male Wistar rats were divided into 3 groups: Control rats, MS rats and MS + HSL rats. MS rats had increased body weight, systolic blood pressure, triglycerides, insulin, HOMA index, and leptin (p ≤ 0.04). Renal function was impaired by an increase in perfusion pressure in the isolated and perfused kidney, albuminuria (p ≤ 0.03), and by a decrease in clearance of creatinine (p ≤ 0.04). The activity of some antioxidant enzymes including the superoxide dismutase isoforms, peroxidases, glutathione peroxidase, glutathione-S-transferase was decreased (p ≤ 0.05). Lipoperoxidation and carbonylation were increased (p ≤ 0.001). The nitrates/nitrites ratio, total antioxidant capacity, glutathione levels and vitamin C were decreased (p ≤ 0.03). The treatment with 2% HSL reversed these alterations. The results suggest that the treatment with 2% HSL infusion protects renal function through its natural antioxidants which favor an improved renal vascular response. The infusion contributes to the increase in the glomerular filtration rate, by promoting an increase in the enzymatic and non-enzymatic antioxidant systems leading to a decrease in OS and reestablishing the normal renal function.
Asunto(s)
Albuminuria/tratamiento farmacológico , Fármacos Antiobesidad/farmacología , Antioxidantes/farmacología , Hibiscus/química , Hipolipemiantes/farmacología , Riñón/efectos de los fármacos , Síndrome Metabólico/tratamiento farmacológico , Albuminuria/sangre , Albuminuria/patología , Animales , Fármacos Antiobesidad/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Ácido Ascórbico/sangre , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Creatinina/sangre , Tasa de Filtración Glomerular/efectos de los fármacos , Glutatión/sangre , Glutatión Peroxidasa/sangre , Glutatión Transferasa/sangre , Hipolipemiantes/aislamiento & purificación , Insulina/sangre , Riñón/metabolismo , Riñón/fisiopatología , Leptina/sangre , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/patología , Extractos Vegetales/química , Ratas , Ratas Wistar , Superóxido Dismutasa/sangre , Triglicéridos/sangreRESUMEN
Cisplatin (CP) is nephrotoxic, and this side effect is used as an animal model for acute kidney injury (AKI). Earlier research has been focused on CP-induced AKI, with relatively little attention being paid to its ability to progress to chronic kidney disease (CKD) on repeated administration. We aimed here to test the dose dependency of its nephrotoxic actions by comparing various physiological, biochemical, molecular, and histopathological indices using repeated increasing doses of CP in rats. Furthermore, we investigated whether these doses of CP would result in the development of CKD. Biochemical, molecular, and histopathological measurements were conducted in plasma, urine, and/or kidneys of rats treated with increasing doses of CP at 1.6, 3.2, and 4.8 mg kg-1 weekly for four consecutive weeks. These doses induced significant and dose-dependent elevations in most of the measured renal indices. These included increased renal fibrosis, as suggested histopathologically and biochemically by the significant increase in transforming growth factor-ß1, significant decrease in actin alpha 2, and variable actions of collagen I and IV. CP also dose-dependently increased nuclear factor (erythroid-derived 2)-like 2 and caspase-3. Multiple repeated doses of CP (1.6 to 4.8 mg kg-1) induced multiple episodes of AKI, leading to CKD after the 4th weekly dose and confirmed that this dosage regimen could be used as an experimental animal model of AKI progressing to CKD. These actions were driven by inflammation, oxidative, and nitrosative stress.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Modelos Animales de Enfermedad , Insuficiencia Renal Crónica/inducido químicamente , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Albuminuria/sangre , Albuminuria/inducido químicamente , Albuminuria/patología , Albuminuria/orina , Animales , Antineoplásicos/efectos adversos , Caspasa 3 , Cisplatino/efectos adversos , Creatinina/sangre , Creatinina/metabolismo , Creatinina/orina , Citocinas , Relación Dosis-Respuesta a Droga , Proteínas de Unión a Ácidos Grasos/metabolismo , Indicán/sangre , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Fósforo/sangre , Ratas Wistar , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Urea/sangre , Ácido Úrico/sangreRESUMEN
Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta-Ins2Akita (KK-Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l-aspartic acid) levels in diabetic KK-Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK-Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK-Akita mice (DKD group), and (c) treated (double-volume Asp diet) KK-Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate-labeled lectins, wheat germ agglutinin (WGA), and anti-endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.
Asunto(s)
Albuminuria/dietoterapia , Ácido Aspártico/administración & dosificación , Nefropatías Diabéticas/dietoterapia , Suplementos Dietéticos , Albuminuria/sangre , Albuminuria/genética , Albuminuria/patología , Animales , Ácido Aspártico/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Modelos Animales de Enfermedad , Endotelio/patología , Endotelio/ultraestructura , Femenino , Membrana Basal Glomerular/patología , Membrana Basal Glomerular/ultraestructura , Humanos , Masculino , Ratones , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Óxido Nítrico Sintasa de Tipo III/análisis , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés OxidativoRESUMEN
The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non-ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin.
Asunto(s)
Compuestos Alílicos/uso terapéutico , Diabetes Mellitus Experimental/dietoterapia , Ajo , Riñón/efectos de los fármacos , Fitoterapia , Aceites de Plantas/uso terapéutico , Estado Prediabético/dietoterapia , Sulfuros/uso terapéutico , Albuminuria/dietoterapia , Albuminuria/metabolismo , Albuminuria/patología , Compuestos Alílicos/administración & dosificación , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Sistemas de Liberación de Medicamentos , Emulsiones , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/orina , Riñón/metabolismo , Riñón/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/orina , Nanotecnología , Aceites de Plantas/administración & dosificación , Polisorbatos , Estado Prediabético/metabolismo , Estado Prediabético/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Sulfuros/administración & dosificación , Tensoactivos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic nephropathy (DN). Several studies demonstrated that puerarin, the active compound of radix puerariae, reduces diabetic injury in streptozotocin (STZ)-induced diabetic rodent models. However, as STZ injection alone results in mild kidney injury, the therapeutic benefit afforded by puerarin in DN remained inconclusive. Thus we sought to clarify the role of puerarin by employing an accelerated DN model, STZ-induced diabetes in the endothelial nitric oxide synthase-null (eNOS-/-) mice. Puerarin treatment of diabetic eNOS-/- mice significantly attenuated albuminuria and diabetic kidney injury, which were associated with reduced oxidative stress and reduced NAPDH oxidase 4 (NOX4) in glomeruli of diabetic eNOS-/- mice. Puerarin treatment of murine podocytes culture in high glucose conditions led to reduced superoxide production and NOX4 expression. We further determined that that puerarin treatment increased both mRNA and protein levels of SIRT1 in podocytes and that puerarin led to SIRT1-mediated deacetylation of NF-κB and suppression of NOX4 expression. Our findings confirm the renoprotective effects of puerarin in an experimental model of advanced DN and provide a molecular mechanism by which puerarin exerts the anti-oxidative effects in podocytes in the diabetic milieu.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Isoflavonas/farmacología , NADPH Oxidasa 4/metabolismo , Podocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Albuminuria/tratamiento farmacológico , Albuminuria/enzimología , Albuminuria/patología , Animales , Células Cultivadas , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/patología , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Podocitos/enzimología , Podocitos/patología , ARN Mensajero/metabolismo , Sirtuina 1/metabolismo , Superóxidos/metabolismoRESUMEN
Prior research has shown that in experimental diabetes mellitus, green tea reduces albuminuria by decreasing podocyte apoptosis through activation of the WNT pathway. We investigated the effect of green tea polyphenols (GTP) on residual albuminuria of diabetic subjects with nephropathy. We conducted a randomised, double-blind study in 42 diabetic subjects with a urinary albumin-creatinine ratio (UACR) >30 mg/g, despite administration of the maximum recommended dose of renin-angiotensin (RAS) inhibition. Patients were randomly assigned to two equal groups to receive either GTP (containing 800 mg of epigallocatechin gallate, 17 with type 2 diabetes and 4 with type 1 diabetes) or placebo (21 with type 2 diabetes) for 12 weeks. Treatment with GTP reduced UACR by 41%, while the placebo group saw a 2% increase in UACR (p = 0.019). Podocyte apoptosis (p = 0.001) and in vitro albumin permeability (p < 0.001) were higher in immortalized human podocytes exposed to plasma from diabetic subjects compared to podocytes treated with plasma from normal individuals. In conclusion, GTP administration reduces albuminuria in diabetic patients receiving the maximum recommended dose of RAS. Reduction in podocyte apoptosis by activation of the WNT pathway may have contributed to this effect.
Asunto(s)
Albuminuria/tratamiento farmacológico , Catequina/análogos & derivados , Nefropatías Diabéticas/tratamiento farmacológico , Pisum sativum/química , Polifenoles/administración & dosificación , Anciano , Albuminuria/metabolismo , Albuminuria/patología , Apoptosis/efectos de los fármacos , Catequina/administración & dosificación , Catequina/química , Células Cultivadas , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Podocitos/metabolismo , Podocitos/patología , Polifenoles/químicaRESUMEN
INTRODUCTION: Cecropia pachystachya (CP) is a plant rich in polyphenols which inhibits the angiotensin-converting enzyme (ACE) in vitro. Angiotensin II (AII) has an important role in the renal lesion provoked by 5/6 nephrectomy (NE). This study evaluated the CP extract effect on renal lesions provoked by 5/6 NE. MATERIALS AND METHODS: Male Wistar rats submitted to 5/6 NE were treated or not treated with CP extract and followed for 90 days. Systemic blood pressure (SBP), albuminuria, renal functional and structural parameters, ACE activity, urinary levels of monocyte chemoattrant protein-1 (MCP-1) and transforming growth factor ß (TGF-ß) were evaluated. RESULTS: Albuminuria and hypertension were less intense in the treated (NE+CP) group compared to the untreated (NE) group. CP extract treatment reduced the fall in glomerular filtration rate observed in NE rats. Glomerulosclerosis, tubulointerstitial lesions, increase of macrophages and AII positive cells in the renal cortex, as well as increases in renal ACE activity, urinary levels of MCP-1 and TGF-ß were attenuated in NE rats by CP treatment. CONCLUSIONS: The treatment with CP extract reduced the SBP and functional and structural renal changes in 5/6 NE rats. These effects were associated with decreased AII expression, ACE activity and inflammation in the renal cortex.
Asunto(s)
Cecropia/química , Riñón/patología , Riñón/cirugía , Nefrectomía , Extractos Vegetales/farmacología , Albuminuria/patología , Albuminuria/orina , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Brasil , Quimiocina CCL2/orina , Inmunohistoquímica , Riñón/efectos de los fármacos , Riñón/fisiopatología , Pruebas de Función Renal , Masculino , Concentración Osmolar , Ratas Wistar , Sístole/efectos de los fármacos , Factor de Crecimiento Transformador beta/orinaRESUMEN
Accumulating evidence suggests that inflammatory processes are involved in the development of diabetic nephropathy (DN). However, there are no effective interventions for inflammation in the diabetic kidneys. Here, we tested the hypothesis that Astragaloside IV(AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bge, ameliorates DN in streptozotocin (STZ)-induced diabetic rats through anti-inflammatory mechanisms. Diabetes was induced with STZ (65 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats were divided into three groups (n=8/each group), namely, diabetic rats, diabetic rats treated with AS-IV at 5 and 10 mgkg(-1)d(-1), p.o., for 8 weeks. The normal rats were chosen as nondiabetic control group (n=8). The rats were sacrificed 10 weeks after induction of diabetes. AS-IV ameliorated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. Renal NF-κB activity, as wells as protein and mRNA expression were increased in diabetic kidneys, accompanied by an increase in mRNA expression and protein content of TNF-α, MCP-1 and ICAM-1 in kidney tissues. The α1-chain type IV collagen mRNA was elevated in the kidneys of diabetic rats. All of these abnormalities were partially restored by AS-IV. AS-IV also decreased the serum levels of TNF-α, MCP-1 and ICAM-1 in diabetic rats. These findings suggest that AS-IV, a novel anti-inflammatory agent, attenuated DN in rats through inhibiting NF-κB mediated inflammatory genes expression.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Regulación de la Expresión Génica , Inflamación/genética , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/genética , FN-kappa B/metabolismo , Saponinas/uso terapéutico , Triterpenos/uso terapéutico , Albuminuria/sangre , Albuminuria/complicaciones , Albuminuria/tratamiento farmacológico , Albuminuria/patología , Animales , Biomarcadores/sangre , Quimiocina CCL2/sangre , Quimiocina CCL2/genética , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/sangre , Inflamación/complicaciones , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/genética , Enfermedades Renales/sangre , Enfermedades Renales/complicaciones , Masculino , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Podocitos/ultraestructura , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Saponinas/farmacología , Triterpenos/farmacología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Diabetic nephropathy (DN) is one of the most common causes of end stage renal disease (ESRD) in China, which requires renal replacement therapy. Recent investigations have suggested an essential role of podocyte injury in the initial stage of DN. This study investigated the potential therapeutic role of genipin, an active extract from a traditional Chinese medicine, on progression of DN in diabetic mice induced by intraperitoneally injection of streptozocin (STZ). In diabetic mice, orally administration of genipin postponed the progression of DN, as demonstrated by ameliorating body weight loss and urine albumin leakage, attenuating glomerular basement membrane thickness, restoring the podocyte expression of podocin and WT1 in diabetic mice. The protective role of genipin on DN is probably through suppressing the up-regulation of mitochondrial uncoupling protein 2 (UCP2) in diabetic kidneys. Meanwhile, through inhibiting the up-regulation of UCP2, genipin restores podocin and WT1 expression in cultured podocytes and attenuates glucose-induced albumin leakage through podocytes monolayer. Therefore, these results revealed that genipin inhibited UCP2 expression and ameliorated podocyte injury in DN mice.
Asunto(s)
Colagogos y Coleréticos/farmacología , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Endopeptidasas/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Iridoides/farmacología , Podocitos/metabolismo , Administración Oral , Albuminuria/tratamiento farmacológico , Albuminuria/etiología , Albuminuria/metabolismo , Albuminuria/patología , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Masculino , Medicina Tradicional China , Ratones , Podocitos/patología , Proteasas Ubiquitina-EspecíficasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis fruit is widely used in Chinese medicine for the treatment of hepatic, renal, heart, cerebrovascular and infectious diseases. AIM OF THE STUDY: To investigate the effects of Schisandra chinensis fruit extract (SE) on albuminuria and podocyte injury as well as the underlying mechanism in the mouse model of streptozotocin (STZ)-induced diabetic nephropathy and in cultured mouse podocyte cells. MATERIALS AND METHODS: SE was orally administrated in STZ-induced diabetic nephropathy mice for 7 weeks, at a daily dose of 5g/kg body weight. The urinary albumin/creatinine ratio and urine albumin excretion rate were measured at the 6th and 9th week of the experiment. The extent of glomerulosclerosis and extracellular matrix deposition were determined by periodic acid-silver methenamine and Masson's trichrome staining. The amount of podocytes and the integrity of the slit diaphragm were detected by immunohistological staining of podocyte markers, Wilms' tumor 1 and nephrin. Alpha-smooth muscle actin, E-cadherin and plasminogen activator inhibitor-1 were measured by western blot and immunohistological staining to evaluate the level of epithelial-to-mesenchymal transition (EMT). Real-time reverse transcription PCR was used to detect the mRNA level of E-cadherin, alpha-SMA and snail in cultured podocyte cells. RESULTS: Treatment with SE significantly decreased the urine albumin excretion rate and urinary albumin/creatinine ratio. In addition, SE attenuated glomerulosclerosis and protected against podocyte loss and integrity of the slit diaphragm. Furthermore, SE effectively prevented the EMT of podocytes caused by diabetic nephropathy. CONCLUSIONS: Our studies suggest that SE might be beneficial for diabetic nephropathy. The effects of SE on attenuating albuminuria and glomerulosclerosis are possibly mediated by preserving podocyte integrity through suppressing EMT.
Asunto(s)
Albuminuria/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Extractos Vegetales/farmacología , Podocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Schisandra , Administración Oral , Albuminuria/etiología , Albuminuria/genética , Albuminuria/metabolismo , Albuminuria/patología , Animales , Biomarcadores/metabolismo , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Frutas , Regulación de la Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Fitoterapia , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Podocitos/metabolismo , Podocitos/patología , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/aislamiento & purificación , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schisandra/química , Factores de TiempoRESUMEN
This study examined renal and glycemic effects of chromium picolinate [Cr(pic)3] supplementation in the context of its purported potential for DNA damage. In preventional protocol, male obese diabetic db/db mice were fed diets either lacking or containing 5, 10 or 100 mg/kg chromium as Cr(pic)3 from 6 to 24 weeks of age; male lean nondiabetic db/m mice served as controls. Untreated db/db mice displayed increased plasma glucose and insulin, hemoglobin A1c, renal tissue advanced glycation end products, albuminuria, glomerular mesangial expansion, urinary 8-hydroxydeoxyguanosine (an index of oxidative DNA damage) and renal tissue immunostaining for γH2AX (a marker of double-strand DNA breaks) compared to db/m controls. Creatinine clearance was lower in untreated db/db mice than their db/m controls, while blood pressure was similar. High Cr(pic)3 intake (i.e., 100-mg/kg diet) mildly improved glycemic status and albuminuria without affecting blood pressure or creatinine clearance. Treatment with Cr(pic)3 did not increase DNA damage despite marked renal accumulation of chromium. In interventional protocol, effects of diets containing 0, 100 and 250 mg/kg supplemental chromium, from 12 to 24 weeks of age, were examined in db/db mice. The results generally revealed similar effects to those of the 100-mg/kg diet of the preventional protocol. In conclusion, the severely hyperglycemic db/db mouse displays renal structural and functional abnormalities in association with DNA damage. High-dose Cr(pic)3 treatment mildly improves glycemic control, and it causes moderate reduction in albuminuria, without affecting the histopathological appearance of the kidney and increasing the risk for DNA damage.
Asunto(s)
Glucemia/metabolismo , Daño del ADN , Diabetes Mellitus Tipo 2/metabolismo , Riñón/efectos de los fármacos , Ácidos Picolínicos/farmacología , Albuminuria/metabolismo , Albuminuria/patología , Animales , Roturas del ADN de Doble Cadena , Diabetes Mellitus Tipo 2/genética , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Histonas/metabolismo , Insulina/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , RatonesRESUMEN
PURPOSE: Diabetic glomerulosclerosis is the hardening of the renal glomeruli that can lead to kidney failure. In the early stage of glomerulosclerosis occur renal mesangial expansion and renal filtration dysfunction. Purple corn has been classified as a functional food and is rich in anthocyanins exerting potential disease-preventive activities. The in vitro study using human renal mesangial cells examined that anthocyanin-rich purple corn butanol fraction (PCB) can attenuate high glucose (HG)-promoted mesangial cell proliferation and matrix accumulation. METHODS: Cells were cultured for 3 days in media containing 33 mM glucose in the presence of 1-20 µg/mL PCB. In the in vivo animal study, db/db mice were treated with 10 mg/kg anthocyanin-rich polyphenolic extracts of purple corn (PCE) for 8 weeks. RESULTS: HG enhanced mesangial production of the fibrosis biomarkers of collagen IV and connective tissue growth factor (CTGF), which was markedly attenuated by adding PCB. Such mesangial fibrosis entailed interleukin-8 activation via eliciting Tyk2-STAT signaling pathway. PCB dampened HG-promoted mesangial hyperplasia that appeared to be attributed to increased expression of platelet-derived growth factor. The 8-week administration of PCE lowered plasma glucose level of db/db mice and ameliorated severe albuminuria. Moreover, PCE lessened collagen fiber accumulation in kidney glomeruli and CTGF expression via retarding TGF-ß signaling. Protein expressions of nephrin and podocin, key proteins for filtration barrier function of the glomerular capillary wall, were repressed by treating mice with PCE. CONCLUSION: Purple corn may be a potent therapeutic agent for the treatment for diabetes-associated glomerulosclerosis accompanying proteinuria and kidney filtration dysfunction.
Asunto(s)
Antocianinas/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Células Mesangiales/efectos de los fármacos , Extractos Vegetales/farmacología , Zea mays/química , Albuminuria/tratamiento farmacológico , Albuminuria/patología , Animales , Biomarcadores/sangre , Glucemia/análisis , Proliferación Celular/efectos de los fármacos , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/patología , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Humanos , Interleucina-8/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Células Mesangiales/metabolismo , Ratones , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteinuria/complicaciones , Proteinuria/tratamiento farmacológico , Proteinuria/patología , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Transducción de Señal , TYK2 Quinasa/genética , TYK2 Quinasa/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Catalase is one of the important antioxidant enzymes regulating the levels of intracellular hydrogen peroxide and hydroxyl radical. The effect of catalase deficiency on progressive renal fibrosis has not been fully elucidated. METHODS: Homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)) were subjected to 5/6 nephrectomy. The functional and morphological alterations of the remnant kidneys, including tubulointerstitial fibrosis, epithelial to mesenchymal transition (EMT), peroxidation, antioxidant enzyme activity, and gene expression of EMT-related molecules were compared between the two groups at 6, 12, and 18 weeks after 5/6 nephrectomy. RESULTS: The 5/6 nephrectomy resulted in albuminuria, decreased renal function, and tubulointerstitial fibrosis with accumulation of type I and type IV collagens in the remnant kidneys of both mouse groups. However, the degree of these changes was significantly higher in acatalasemic mice after 5/6 nephrectomy as compared with wild-type mice until week 18. EMT, a crucial phenotypic alteration of tubular epithelial cells, was observed in acatalasemic mice by electron microscopy and was associated with upregulation of EMT-related alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), and fibroblast specific protein-1 (FSP-1) gene expression. Significant increases in the tubulointerstitial deposition of lipid peroxidation products, including 4-hydroxy-2-nonenal and urinary excretion of 8-hydroxy-2'- deoxyguanosine were observed in the acatalasemic mice after 5/6 nephrectomy as compared with the wild-type mice. Glomerular sclerosis developed after tubulointerstitial injury in acatalasemic mice. The level of catalase activity remained low in the remnant kidneys of acatalasemic mice until week 18 without compensatory up-regulation of glutathione peroxidase or superoxide dismutase (SOD) activity. Finally, supplementation of a SOD mimetic tempol did not prevent peroxidation and tubulointerstitial fibrosis in the acatalasemic remnant kidneys. CONCLUSION: These findings indicate that acatalasemia exacerbates renal oxidant tissue injury and sensitizes remnant kidneys to EMT and progressive renal fibrosis. This study suggests a central role for catalase in the defense against oxidant-mediated renal fibrosis.
Asunto(s)
Catalasa/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Estrés Oxidativo/fisiología , Albuminuria/metabolismo , Albuminuria/patología , Animales , Antioxidantes/farmacología , Presión Sanguínea , Peso Corporal , Catalasa/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo IV/genética , Óxidos N-Cíclicos/farmacología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibrosis , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Masculino , Mesodermo/metabolismo , Mesodermo/patología , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Nefrectomía , Tamaño de los Órganos , Estrés Oxidativo/efectos de los fármacos , Marcadores de Spin , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Inducible, high-output nitric oxide (NO) production has been identified as a central mediator of cell injury in immune-mediated renal disease. In acute anti-thy-1 glomerulonephritis prefeeding with the NO precursor L-arginine increases mesangial cell injury and the subsequent fibrosis. The present study tested the hypothesis that L-arginine supplementation may also be detrimental in chronic, NO-mediated murine lupus nephritis. METHODS: Groups (N = 18) of female MRL/lpr mice with lupus nephritis were fed the following diets: (1) normal protein (22% casein); (2) normal protein and 1.0% L-arginine in the drinking water; (3) low protein (6% casein); (4) low protein + 0.4%l-arginine; and (5) low protein + 1.0% L-arginine. After 40 days mouse survival, albuminuria, matrix accumulation, inflammatory cell infiltration, immunoglobulin G (IgG) deposition, expression of transforming growth factor-beta 1 (TGF-beta 1), fibronectin and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein, anti-DNA antibody titer, inducible nitric oxide synthase (iNOS) mRNA expression, blood amino acid levels, blood urea nitrogen (BUN) concentrations and blood and urinary NOx (nitrite + nitrate) levels were assessed. RESULTS: L-Arginine supplementation increased mortality significantly (P < 0.02). The death rate increased from 0% in the lowest to 50% in the highest L-arginine intake group (normal protein + 1.0% L-arginine). L-Arginine administration increased albuminuria, renal matrix accumulation, TGF-beta 1, fibronectin, PAI-1, blood L-arginine, L-citrulline, BUN and blood and urine NOx levels, while protein restriction reduced these parameters. Renal cell infiltration and iNOS mRNA expression were decreased in the low protein group only. Anti-ds DNA-IgG and renal IgG deposition were comparable in all groups CONCLUSIONS: Increasing L-arginine intake increases the severity of renal fibrosis and the likelihood of death in MRL/lpr mice. The results appear to be at least in part mediated through enhanced cytotoxic NO generation via iNOS. The data suggest that L-arginine restriction should be considered in human immune-mediated renal diseases.
Asunto(s)
Arginina/farmacología , Nefritis Lúpica/mortalidad , Nefritis Lúpica/patología , Albuminuria/inmunología , Albuminuria/mortalidad , Albuminuria/patología , Aminoácidos/sangre , Animales , Autoanticuerpos/sangre , Nitrógeno de la Urea Sanguínea , ADN/inmunología , Matriz Extracelular/patología , Femenino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis , Inmunoglobulina G/metabolismo , Leucocitos Mononucleares/patología , Nefritis Lúpica/inmunología , Ratones , Ratones Endogámicos MRL lpr , Nitratos/sangre , Nitratos/orina , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Nitritos/sangre , Nitritos/orina , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , ARN Mensajero/análisis , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1RESUMEN
Extracellular matrix (ECM) accumulation in the glomerular mesangium is a characteristic feature of diabetic nephropathy. While transforming growth factor-beta1 (TGF-beta1) is the final mediator of ECM accumulation, reactive oxygen species (ROS) and protein kinase C (PKC) are the upstream signaling molecules that mediate hyperglycemia-induced ECM expansion. Magnesium lithospermate B (LAB) is an active component isolated from Salvia miltiorrhizae with known renoprotective properties due to its antioxidative effects. Thus, the present study examined the effects of LAB on renal injury in streptozotocin-induced diabetic rats (STZR) and on the activation of mesangial cells cultured under high glucose conditions. Ten micrtograms of LAB/kg per day was started 8 wk after streptozotocin injection and continued for a period of 8 wk. It significantly suppressed renal malondialdehyde (MDA), microalbuminuria, glomerular hypertrophy, mesangial expansion, and the upregulation of renal TGF-beta1, fibronectin, and collagen in STZR without significantly affecting plasma glucose. Both 30 mM of glucose and 100 uM of H(2)O(2) significantly increased TGF-beta1 and fibronectin protein secretion by mesangial cells. LAB at 10 micro g/ml inhibited high glucose- and H(2)O(2)-induced TGF-beta1 and fibronectin secretion. LAB also inhibited glucose-induced intracellular ROS generation and PKC activation in mesangial cells, but it did not directly inhibit PKC activity at dosages that inhibited ROS generation. The in vitro data of this study show that LAB inhibits ROS generation leading to PKC activation and TGF-beta1 and fibronectin upregulation in mesangial cells cultured under high glucose conditions. Moreover, delayed treatment with LAB was found to significantly suppress the progression of renal injury in STZR. LAB may become a new therapeutic agent for the treatment of diabetic nephropathy.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Depuradores de Radicales Libres/farmacología , Albuminuria/tratamiento farmacológico , Albuminuria/metabolismo , Albuminuria/patología , Animales , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Medicamentos Herbarios Chinos/química , Fibronectinas/metabolismo , Depuradores de Radicales Libres/química , Mesangio Glomerular/metabolismo , Mesangio Glomerular/patología , Glucosa/farmacología , Peróxido de Hidrógeno/farmacología , Masculino , Oxidantes/farmacología , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1RESUMEN
The objective of this study was to compare the effect of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker on the development of renal changes in diabetic rats. Diabetes was induced by an intravenous injection of streptozotocin in normotensive Wistar rats. Treatment was commenced immediately in 1 set of rats with 4 treatment arms: nitrendipine (250 mg/kg fodder), enalapril (35 mg/L drinking water), both treatments in combination, or placebo. Treatment was continued for 9 weeks. Another set of rats was left with untreated diabetes for 3 months followed by 7 weeks treatment as above. When starting treatment right after induction of diabetes, nitrendipine significantly reduced urinary albumin excretion (UAE) to the nondiabetic level (P < .05) without reducing blood pressure (BP), whereas enalapril failed to significantly reduce UAE despite a reduction in BP. Combining the two treatments showed no further reduction in UAE compared to monotherapy with nitrendipine, despite a lower BP. When leaving diabetic rats untreated for 3 months, only the coadministration of nitrendipine and enalapril showed a significant reduction in UAE compared to monotherapy and placebo treatment, but showed no significant effect on BP.