RESUMEN
OBJECTIVE: We hypothesised that vitamin D has a beneficial renal protective effect from diabetic nephropathy (DN). METHODS: Four rat groups were included: normal control (control), type 2 diabetes for eight weeks (DM), treated group with angiotensin receptor blocker losartan (DM + L), and vitamin D-treated group started from the onset of diabetes (DM + Vit D). RESULTS: In the both treated groups, we found a significant (p < .05) reduction in the renal pro-inflammatory and profibrotic markers induced by diabetes. Vitamin D caused more reduction in monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGFß-1), and renin-angiotensin levels that gave better kidney function compared to the DM + L group. CONCLUSION: Vitamin D may have a valuable role in the renal protective effect from DN, this may occur via expression of its VDR, Klotho and blocking renin-angiotensin activation, so vitamin D should be considered as a target in renal prophylactic measures against DN.
Asunto(s)
Nefropatías Diabéticas/prevención & control , Suplementos Dietéticos , Regulación de la Expresión Génica , Glucuronidasa/metabolismo , Riñón/metabolismo , Insuficiencia Renal/prevención & control , Vitamina D/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Biomarcadores/sangre , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Regulación hacia Abajo , Glucuronidasa/química , Glucuronidasa/genética , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/fisiopatología , Proteínas Klotho , Losartán/uso terapéutico , Masculino , Distribución Aleatoria , Ratas Wistar , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Insuficiencia Renal/complicaciones , Insuficiencia Renal/inmunología , Insuficiencia Renal/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Reproducibilidad de los ResultadosRESUMEN
Doxorubicin (DXR) is one of the most important chemotherapeutic agent. However, nephrotoxicity reduces its clinical utility in humans. The aim of the study was to investigate protective effects of curcumin (CMN) against DXR-induced nephrotoxicity. Rats were subjected to oral treatment of CMN (100 and 200 mg/kg body weight) for 7 days. Nephrotoxicity was induced by single intra peritoneal injection of DXR (40 mg/kg body weight) on the fifth day and then the experiment was terminated on the eighth day. Nephroprotective effects of CMN were associated with decrease in serum toxicity markers and increase in antioxidant enzyme activities. CMN was able to reduced the levels of inflammatory markers such as TNF-α, NF-κB, IL-1ß, iNOS and COX-2 in the rats. It also reduced the expressions of apoptotic marker including caspase-3, and oxidative DNA damage marker including 8-OHdG. Collectively, these findings indicated that CMN protect against DXR-induced nephrotoxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Curcumina/uso terapéutico , Doxorrubicina/antagonistas & inhibidores , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Insuficiencia Renal/prevención & control , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/química , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/uso terapéutico , Biomarcadores/sangre , Biomarcadores/metabolismo , Curcumina/administración & dosificación , Curcumina/efectos adversos , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Daño del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/efectos adversos , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Oxidación-Reducción , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/efectos adversos , Distribución Aleatoria , Ratas Wistar , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/inmunología , Insuficiencia Renal/metabolismo , Inhibidores de Topoisomerasa II/efectos adversos , Inhibidores de Topoisomerasa II/químicaRESUMEN
OBJECTIVE: To investigate the correlation between the clinical effects of Huangqi (Astragalus membranaceus) on different stages of diabetic nephropathy (DN) and the pharmacological effect of Huangqi on the activity of inducible nitric oxide synthase (iNOS) in macrophages in different states. METHODS: The PubMed, China National Knowledge Infrastructure, and Wanfang databases were searched. Clinical data was sourced from papers on treatment of different stages of DN with Huangqi, and pharmacological data was from papers on the effects of Huangqi on the iNOS activity of macrophages in a resting or an activated state. RESULTS: Meta-analysis of Huangqi injections on stages III and III-IV DN and randomized controlled trials on other stages showed that Huangqi had therapeutic effects on different stages of DN and on macrophages in different states: inducing normal macrophages in a resting state to generate nitric oxide (NO), tumor necrosis factor-α, and so forth upon iNOS activation; inhibiting NO generation by normal lipopolysaccharide- (LPS-) activated macrophages; and enhancing NO generation by LPS-induced macrophages from patients with renal failure. CONCLUSIONS: Huangqi can regulate iNOS activity of macrophages in different states in vitro. These biphasic or antagonistic effects may explain why Huangqi can be used to treat different stages of DN.
Asunto(s)
Astragalus propinquus/inmunología , Mezclas Complejas/uso terapéutico , Nefropatías Diabéticas/terapia , Macrófagos/fisiología , Medicina Tradicional China , Óxido Nítrico Sintasa de Tipo II/metabolismo , Insuficiencia Renal/terapia , Nefropatías Diabéticas/inmunología , Progresión de la Enfermedad , Activación Enzimática , Humanos , Óxido Nítrico/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal/inmunologíaRESUMEN
Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1ß), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for cisplatin.
Asunto(s)
Antineoplásicos/efectos adversos , Antioxidantes/uso terapéutico , Catequina/análogos & derivados , Cisplatino/efectos adversos , Riñón/efectos de los fármacos , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Catequina/farmacología , Catequina/uso terapéutico , Línea Celular , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/inmunología , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Renal/inmunología , Insuficiencia Renal/metabolismoRESUMEN
Regulatory T cells (Tregs) can suppress immunologic damage in renal ischemia-reperfusion injury (IRI), but the isolation and ex vivo expansion of these cells for clinical application remains challenging. Here, we investigated whether the IL-2/anti-IL-2 complex (IL-2C), a mediator of Treg expansion, can attenuate renal IRI in mice. IL-2C administered before bilateral renal IRI induced Treg expansion in both spleen and kidney, improved renal function, and attenuated histologic renal injury and apoptosis after IRI. Furthermore, IL-2C administration reduced the expression of inflammatory cytokines and attenuated the infiltration of neutrophils and macrophages in renal tissue. Depletion of Tregs with anti-CD25 antibodies abrogated the beneficial effects of IL-2C. However, IL-2C-mediated renal protection was not dependent on either IL-10 or TGF-ß. Notably, IL-2C administered after IRI also enhanced Treg expansion in spleen and kidney, increased tubular cell proliferation, improved renal function, and reduced renal fibrosis. In conclusion, these results indicate that IL-2C-induced Treg expansion attenuates acute renal damage and improves renal recovery in vivo, suggesting that IL-2C may be a therapeutic strategy for renal IRI.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Complejo Antígeno-Anticuerpo/fisiología , Diferenciación Celular/inmunología , Interleucina-2/fisiología , Insuficiencia Renal/prevención & control , Daño por Reperfusión/prevención & control , Linfocitos T Reguladores/inmunología , Animales , Evaluación Preclínica de Medicamentos , Fibrosis , Interleucina-2/inmunología , Riñón/inmunología , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Insuficiencia Renal/inmunología , Insuficiencia Renal/patología , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patologíaRESUMEN
OBJECTIVE: To evaluate the preclinical erythropoiesis stimulating properties of Hematide, a novel, PEGylated, synthetic peptide for the treatment of anemia associated with chronic kidney disease and cancer. METHODS: The in vitro activity of Hematide was assessed in competitive binding, proliferation, signal transduction, and apoptosis assays, and in erythroid colony-forming assays with CD34(+) cells purified from human bone marrow. Erythropoiesis and pharmacokinetics were evaluated in rat, monkey, and a rat chronic renal insufficiency (CRI) model following single administration. Erythropoiesis and immunogenicity were also evaluated following repeat administration in rats. RESULTS: Hematide binds and activates the erythropoietin receptor and causes proliferation and differentiation of erythroid progenitor cells. Sustained circulatory persistence of Hematide is observed in rats and monkeys. In a rat CRI model, Hematide exhibited twofold lower clearance than in the normal rat, with hypothesis consistent with Hematide being cleared, at least partially, via the kidney. A dose-dependent rise in hemoglobin (Hgb) and duration of response was observed following single administration in rats and monkeys. Hematide was able to alleviate anemia in an experimental CRI rodent model. Repeat intravenous (IV) and subcutaneous (SC) administration in rats yielded similar erythrogenic responses, with no anti-Hematide antibodies being detected. CONCLUSIONS: Hematide is a potent erythropoiesis stimulating agent with a prolonged half-life and slow clearance times. It is anticipated that similar prolonged clearance and activity will be observed in the clinic, potentially enabling dosing intervals of 3 to 4 weeks that may translate into improved patient convenience for the treatment of anemia.