RESUMEN
Shensu IV is a Chinese prescription well-known for its function in treating chronic kidney diseases. However, the potential mechanisms underlying how Shensu IV exerts its effects remain unclear. In the present study, we investigated the effects of Shensu IV on glomerular podocyte injury in nephrotic rats and puromycin-induced injury in cultured podocytes, and assessed the associated molecular mechanisms. Liquid chromatography-mass spectrometry (LC-MS) results showed that the main components of Shensu IV were l-Carnitine, P-lysoPC (LPC) 16:0, Coumaroyl tyramine, Tetramethylpyrazine, LPC 18:1, Choline, (S,S)-Butane-2,3-diol, and Scopoletin. We further found that nephrotic rats displayed pathological alterations in kidney tissues and ultrastructural changes in glomerular podocytes; however, these effects were reversed with Shensu IV treatment. Compared with the control, the numbers of autophagosomes were markedly reduced in the model group, but not in the Shensu IV treatment group. Furthermore, the expression of p62 was significantly higher in the model group than in the controls, whereas the LC3-II/I ratio was significantly lower; however, these changes were not observed when Shensu IV was administered. The protective effects of Shensu IV were further confirmed in podocytes displaying puromycin-induced injury. Compared with control group, the expression of long non-coding RNA (lncRNA) H19, mTOR, p-mTOR, and p62 was significantly increased in the puromycin group, whereas that of distinct subgroup of the RAS family member 3 (DIRAS3) was significantly decreased, as was the LC3-II/I ratio. The opposite results were obtained for both shH19- and Shensu IV-treated cells. Collectively, our data demonstrated that Shensu IV can prevent glomerular podocyte injury in nephrotic rats and puromycin-treated podocytes, likely via promoting lncRNA H19/DIRAS3-regulated autophagy.
Asunto(s)
Autofagia , Medicamentos Herbarios Chinos/uso terapéutico , Nefrosis/tratamiento farmacológico , Podocitos/efectos de los fármacos , ARN Largo no Codificante/metabolismo , Proteínas de Unión al GTP rho/genética , Animales , Células Cultivadas , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Nefrosis/etiología , Nefrosis/prevención & control , Podocitos/metabolismo , Puromicina/toxicidad , ARN Largo no Codificante/genética , Ratas , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Unión al GTP rho/metabolismoRESUMEN
The burden and morbidity of environmental nephrosis is increasing globally. Atrazine (ATR) and degradation products in the environment are considered key determinants of nephrosis. However, the lack of highly effective treatments for environmental nephrosis creates an urgent need to better understand the preventive strategies and mechanisms. This study aimed to highlight the mechanism of ATR-induced environmental nephrosis and the chemoprotective potential of lycopene (LYC) against the renal injury and nephrosis. Male mice were treated with LYC (5 mg/kg) and/or ATR (50 mg/kg or 200 mg/kg) by gavage administration for 21 days. Histopathological changes and biochemical function, cytochrome P450 enzymes system (CYP450s), nuclear xenobiotic receptors (NXRs) response and the transcription of CYP isoforms (CYPs) were detected. ATR exposure caused the changes of the histopathological and biochemical function, activated the NXR response and disturbed the CYP450s homeostasis. Supplementary LYC significantly prevented ATR-induced nephrotoxicity and alleviated the alternation of histopathological and biochemical function via modulating the CYP450s homeostasis and the NXR response. The results demonstrated AHR, CAR, PXR, PPAR (α, γ), CYP1, CYP2, CYP3 and CYP4 superfamily play a vital role in LYC-ATR interaction. Our findings provide new evidence that ATR exposure can cause the environmental nephrosis via inducing the kidney injury. Supplementary LYC showed significant chemoprotective potential against ATR-induced renal injury and environmental nephrosis via regulating the NXR response and the CYP450s homeostasis.
Asunto(s)
Antioxidantes/uso terapéutico , Atrazina/toxicidad , Carotenoides/uso terapéutico , Herbicidas/toxicidad , Nefrosis/prevención & control , Intoxicación/fisiopatología , Receptores de Esteroides/antagonistas & inhibidores , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Animales no Consanguíneos , Atrazina/administración & dosificación , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patología , Receptor de Androstano Constitutivo , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Herbicidas/administración & dosificación , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Licopeno , Masculino , Ratones , Nefrosis/etiología , Intoxicación/metabolismo , Intoxicación/patología , Receptor X de Pregnano , Análisis de Componente Principal , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Esteroides/agonistas , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismoRESUMEN
BACKGROUND: Yi Qi Qing Re Gao (YQQRG) formula is a traditional Chinese herbal medicine used to treat chronic nephritis. This study was designed to evaluate the underlying mechanism in the use of YQQRG formula to treat nephrosis induced by puromycin aminonucleoside (PAN). METHODS: Thirty-six male Wistar rats were randomly divided into 3 groups of 12 rats each: a sham group, a vehicle-treated PAN model group (PAN), and a group treated with YQQRG (PAN + YQQRG). The PAN model was established by a single intravenous injection of PAN at a dose of 40 mg/kg body weight; rats in the sham group received the same volume of saline. Twenty-four hour urinary protein was measured 0, 3, 5, 10, and 15 days after the injection. The rats were sacrificed on day 10 and day 15 and the serum lipid profile examined. The renal cortex of each rat was stained with periodic acid-Schiff reagent and the pathologic alterations and ultrastructural changes were examined by transmission electron microscopy. In situ cell apoptosis was detected by a terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) assay. Transcriptive levels of inflammatory markers and molecules associated with apoptosis were detected by a real-time polymerase chain reaction and expression of proteins was examined by either immunohistochemistry or Western blot analysis. RESULTS: YQQRG significantly decreased urinary protein level, and lowered serum lipid level. YQQRG also attenuated histologic lesions in the rat kidneys. Activation of inflammatory markers was largely restored by the administration of YQQRG. TUNEL assay showed that YQQRG decreased the number of apoptotic cells. Both mRNA and protein levels of caspase-3 were significantly reduced in the group treated with YQQRG, whereas expression of the Bcl-2 protein increased in the YQQRG group. CONCLUSIONS: YQQRG alleviated kidney injury in PAN-treated rats, possibly through anti-inflammatory and anti-apoptotic effects.
Asunto(s)
Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Inflamación/tratamiento farmacológico , Riñón/efectos de los fármacos , Nefritis/prevención & control , Nefrosis/prevención & control , Fitoterapia , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Caspasa 3/genética , Caspasa 3/metabolismo , Medicamentos Herbarios Chinos/farmacología , Inmunohistoquímica , Riñón/metabolismo , Riñón/patología , Masculino , Microscopía Electrónica de Transmisión , Nefritis/metabolismo , Nefrosis/inducido químicamente , Nefrosis/metabolismo , Puromicina Aminonucleósido , Qi , ARN Mensajero/metabolismo , Ratas Wistar , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The pathophysiology of contrast-induced AKI (CIAKI) is incompletely understood due to the lack of an appropriate in vivo model that demonstrates reduced kidney function before administration of radiocontrast media (RCM). Here, we examine the effects of CIAKI in vitro and introduce a murine ischemia/reperfusion injury (IRI)-based approach that allows induction of CIAKI by a single intravenous application of standard RCM after injury for in vivo studies. Whereas murine renal tubular cells and freshly isolated renal tubules rapidly absorbed RCM, plasma membrane integrity and cell viability remained preserved in vitro and ex vivo, indicating that RCM do not induce apoptosis or regulated necrosis of renal tubular cells. In vivo, the IRI-based CIAKI model exhibited typical features of clinical CIAKI, including RCM-induced osmotic nephrosis and increased serum levels of urea and creatinine that were not altered by inhibition of apoptosis. Direct evaluation of renal morphology by intravital microscopy revealed dilation of renal tubules and peritubular capillaries within 20 minutes of RCM application in uninjured mice and similar, but less dramatic, responses after IRI pretreatment. Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 (RIP1) kinase domain, prevented osmotic nephrosis and CIAKI, whereas an inactive Nec-1 derivate (Nec-1i) or the pan-caspase inhibitor zVAD did not. In addition, Nec-1 prevented RCM-induced dilation of peritubular capillaries, suggesting a novel role unrelated to cell death for the RIP1 kinase domain in the regulation of microvascular hemodynamics and pathophysiology of CIAKI.
Asunto(s)
Lesión Renal Aguda/prevención & control , Imidazoles/uso terapéutico , Indoles/uso terapéutico , Túbulos Renales/efectos de los fármacos , Nefrosis/prevención & control , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Lesión Renal Aguda/inducido químicamente , Animales , Muerte Celular , Línea Celular , Medios de Contraste/toxicidad , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Imidazoles/farmacología , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Nefrosis/inducido químicamente , Daño por Reperfusión/complicacionesRESUMEN
Effects of green tea catechins comprising EGCg, EGC, ECg, EC, GCg, GC, Cg, and C were determined on blood glucose tolerance and oxidative stress status in type 2 diabetic Goto-Kakizaki (GK) rats. GK rats fed the catechin-containing diet tended to maintain blood glucose and systolic blood pressure at lower levels in the latter stages of the feeding period of 76 d, compared to those not receiving dietary catechins (control group). The blood glucose tolerance test performed on days 48-49 showed that GK rats fed the catechins had lower blood glucose levels than GK rats not fed catechins during the 120 min after glucose loading. In catechin-fed rats, amounts of 8-OH dG and albumin excreted into the urine determined on days 71-72, and kidney ACE activity determined on day 76, were lower than those in control rats. From these results it is concluded that dietary catechins may be effective in delaying the progression of diabetes and the associated oxidative stress.
Asunto(s)
Glucemia/efectos de los fármacos , Catequina/farmacología , Intolerancia a la Glucosa/dietoterapia , Estrés Oxidativo/efectos de los fármacos , Té , Adiponectina/sangre , Alimentación Animal , Animales , Presión Sanguínea/efectos de los fármacos , Nefropatías Diabéticas/prevención & control , Insulina/sangre , Riñón/metabolismo , Hígado/metabolismo , Masculino , Nefrosis/prevención & control , Ratas , Ratas Endogámicas , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Triglicéridos/sangreRESUMEN
The only treatment proposed after human contamination with MOX (mixed oxide of uranium and plutonium) is diethylenetriaminepentaacetic acid (DTPA), because plutonium is considered to be the major risk. However, both DTPA and uranium are nephrotoxic at high dosages and DTPA has been shown to increase in vitro the cytotoxicity induced by uranium on cultured epithelial tubular cells. This work aimed to test this effect in vivo. Rats were injected with subtoxic (57 microg kg(-1)) to toxic (639 microg kg(-1)) amounts of uranium as nitrate at 0 h, they received two DTPA injections (30 micromol kg(-1)) at 2 min and 24 h and were euthanased at 48 h. The nephrotoxic effects were evaluated by measurement of the body weight gain, food and water intake, measurement of biochemical parameters in urine and blood, and histological examination of one kidney. The main result was that DTPA did not increase the nephrotoxicity induced by uranium in the range of concentrations tested, which was inconsistent with the in vitro results.
Asunto(s)
Terapia por Quelación/métodos , Nefrosis/tratamiento farmacológico , Nefrosis/patología , Ácido Pentético/administración & dosificación , Ácido Pentético/efectos adversos , Uranio/toxicidad , Animales , Quelantes/administración & dosificación , Quelantes/efectos adversos , Descontaminación/métodos , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Sinergismo Farmacológico , Epitelio/efectos de los fármacos , Epitelio/patología , Epitelio/efectos de la radiación , Inyecciones Intraperitoneales , Riñón/efectos de los fármacos , Riñón/patología , Riñón/efectos de la radiación , Masculino , Nefrosis/etiología , Nefrosis/prevención & control , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Uranio/análisis , Uranio/farmacocinéticaRESUMEN
OBJECTIVE: To explore the mechanism of protective effect of Compound Salvia Injection (CSI) on experimental cyclosporin A induced nephrotoxicity. METHODS: Rats were on low-salt diet and cyclosporin A (CsA) was administered once a day through gastrogavage at dosage of 30 mg/kg.d for 28 days. Expression of the mRNA for intrarenal transforming growth factor-beta 1 (TGF-beta 1) and renin was measured by reverse transcription-polymerase chain reaction (RT-PCR). Intrarenal expression of TGF-beta 1 and Collagen IV was determined by immunohistochemical assays. The effects of CSI on these changes were also evaluated. RESULTS: Chronic CsA-induced nephropathy might be correlated to TGF-beta 1 and renin mRNA up-regulation as well as matric proteins accumulation in interstitium. CSI could reduce these changes. CONCLUSION: Decreased CsA-related TGF-beta 1 and renin upregulation expression and accumulation of matrix proteins in the kidney might be related to the protective mechanism of CSI on CsA-induced chronic nephrotoxicity.
Asunto(s)
Colágeno Tipo IV/biosíntesis , Medicamentos Herbarios Chinos/farmacología , Nefrosis/metabolismo , Fitoterapia , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Enfermedad Crónica , Colágeno Tipo IV/genética , Ciclosporina , Masculino , Nefrosis/inducido químicamente , Nefrosis/prevención & control , Extractos Vegetales , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Renina/biosíntesis , Renina/genética , Salvia miltiorrhiza , Factor de Crecimiento Transformador beta/genéticaRESUMEN
OBJECTIVE: To determine whether supplemental i.v. calcium administration would attenuate or prevent gentamicin-induced acute renal failure, defined as an increase in serum creatinine concentration > or = 50% above baseline. ANIMALS: 10 healthy pony mares. PROCEDURE: Pony mares were randomly assigned to receive calcium at a dosage of 20 mg/kg of body weight or saline solution i.v., twice daily for 14 days. All pony mares received gentamicin at a dosage of 20 mg/kg i.v. every 8 hours for 14 days. Gentamicin pharmacokinetic, serum biochemical, and urinalysis data were measured every other day for the 14-day study period. Renal histologic examination was performed, and results were scored at the end of the 14-day period. RESULTS: 4 of 5 mares not receiving calcium supplementation developed acute renal failure. Only 1 of the 5 mares receiving calcium supplementation developed acute renal failure. Over the course of the study, pony mares receiving calcium supplementation had significantly fewer changes in urinalysis variables, and significantly less microscopic renal damage. CONCLUSION: Daily i.v. administration of calcium attenuated gentamicin-induced acute renal failure. CLINICAL RELEVANCE: Calcium supplementation may help diminish the risk of acute renal failure associated with aminoglycoside antibiotics.