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OBJECTIVE: Shenkang injection (SKI) has been widely used in China for many years for the treatment of kidney disease. The objective of this systematic review was to assess the efficacy of Shenkang injection for the treatment of acute kidney injury (AKI). METHODS: A search was conducted across seven databases, encompassing data from the inception of each database through October 8th, 2023. Randomized controlled trials comparing SKI-treated AKI patients with control subjects were extracted. The main outcome measure was serum creatinine (SCr) levels. Secondary outcomes included blood urea nitrogen (BUN), serum cystatin C (CysC), 24-h urine protein (24 h-Upro) levels, APACHE II score and adverse reactions. RESULTS: This meta-analysis included eleven studies, and the analysis indicated that, compared with the control group, SKI significantly decreased SCr [WMD = -23.31, 95% CI (-28.06, -18.57); p < 0.001]; BUN [WMD = -2.07, 95% CI (-2.56, -1.57); p < 0.001]; CysC [WMD = -0.55, 95% CI (-0.78, -0.32), p < 0.001]; 24-h urine protein [WMD = -0.43, 95% CI (-0.53, -0.34), p < 0.001]; and the APACHE II score [WMD = -3.07, 95% CI (-3.67, -2.48), p < 0.001]. There was no difference in adverse reactions between the SKI group and the control group [RR = 1.32, 95% CI (0.66, 2.63), p = 0.431]. CONCLUSION: The use of SKI in AKI patients may reduce SCr, BUN, CysC, 24-h Upro levels, and APACHE II scores in AKI patients. The incidence of adverse reactions did not differ from that in the control group. Additional rigorous clinical trials will be necessary in the future to thoroughly evaluate and establish the effectiveness of SKI in the treatment of AKI.
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Injúria Renal Aguda , Nitrogênio da Ureia Sanguínea , Creatinina , Medicamentos de Ervas Chinesas , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Injúria Renal Aguda/tratamento farmacológico , APACHE , Creatinina/sangue , Cistatina C/sangue , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/efeitos adversos , Injeções , Resultado do TratamentoRESUMO
Renal interstitial fibrosis (RIF) is the main pathological basis for the progression of chronic kidney disease (CKD), however, effective interventions are limited. Here, we investigated the effect of Icariside II (ICA-II) on RIF and explored the underlying mechanisms. Rats receiving 5/6 ablation and infarction (A/I) surgery were gavaged with ICA-II (5 or 10 mg/kg) for 8 weeks. In vitro, TGF-ß1-stimulated NRK-52E cells were treated with ICA-II and (or) oleic acid, etomoxir, ranolazine, fenofibrate, and GW6471. The effects of ICA-II on RIF, fatty acid oxidation, lipid deposition, and mitochondrial function were determined by immunoblotting, Oil red O staining, colorimetric, and fluorometric assays. Using adeno-associated virus injection and co-culture methods, we further determined mechanisms of ICA-II anti-RIF. ICA-II ameliorated the fibrotic responses in vivo and in vitro. RNA-seq analysis indicated that ICA-II regulated fatty acid degradation and PPAR pathway in 5/6 (A/I) kidneys. ICA-II attenuated lipid accumulation and up-regulated expression of PPARα, CPT-1α, Acaa2, and Acadsb proteins in vivo and in vitro. Compared to ICA-II treatment, ICA-II combined with Etomoxir exacerbated mitochondrial dysfunction and fibrotic responses in TGF-ß-treated NRK-52E cells. Importantly, we determined that ICA-II improved lipid metabolism, fatty acid oxidation, mitochondrial function, and RIF by restoring PPARα. Co-culture revealed that ICA-II decreased the expression of Fibronectin, Collagen-I, α-SMA, and PCNA proteins in NRK-49F cells by restoring PPARα of renal tubular cells. ICA-II may serve as a promising therapeutic agent for RIF in 5/6 (A/I) rats, which may be important for the prevention and treatment of CKD.
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Compostos de Epóxi , Flavonoides , Nefropatias , Insuficiência Renal Crônica , Ratos , Animais , PPAR alfa/metabolismo , Linhagem Celular , Nefropatias/tratamento farmacológico , Rim , Fator de Crescimento Transformador beta1/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Ácidos Graxos/farmacologia , Metabolismo dos Lipídeos , Fibrose , LipídeosRESUMO
The purpose of this study was to investigate the effect of notoginsenoside R_1(NGR_1) on alleviating kidney injury by regulating renal oxidative stress and the Nrf2/HO-1 signaling pathway in mice with IgA nephropathy(IgAN) and its mechanism. The mouse model of IgAN was established using a variety of techniques, including continuous bovine serum albumin(BSA) gavage, subcutaneous injections of carbon tetrachloride(CCl_4) castor oil, and tail vein injections of lipopolysaccharide(LPS). After successful modeling, mice with IgAN were randomly separated into a model group, low, medium, and high-dose NGR_1 groups, and a losartan group, and C57BL6 mice were utilized as normal controls. The model and normal groups were given phosphate buffered saline(PBS) by gavage, the NGR_1 groups were given varying dosages of NGR_1 by gavage, and the losartan group was given losartan by gavage for 4 weeks. The 24-hour urine of mice was collected after the last administration, and serum and kidney tissues of mice were taken at the end of the animal experiment. Then urine red blood cell count(URBCC), 24-hour urine protein(24 h protein), serum creatinine(Scr), and blood urea nitrogen(BUN) levels were measured. The enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of galactose-deficient IgA1(Gd-IgA1), kidney injury molecule 1(Kim-1), and neutropil gelatinase-associated lipocalin(NGAL) in the mouse serum. The assay kits were used to detect the levels of malondialdehyde(MDA) and superoxide dismutase(SOD), and immunofluorescence(IF) was used to detect the expression level of glutathione peroxidase 4(GPX4) in the mesangial region. Western blot was used to detect the protein expression of nuclear transcription factor E2 related factor 2(Nrf2)/heme oxygenase 1(HO-1) signaling pathway in the renal tissue. Hematoxylin-eosin(HE) staining was used to observe pathological alterations in the glomerulus of mice. The results revealed that, as compared with the model group, the serum Gd-IgA1 level, URBCC, 24 h protein level, renal damage markers(Kim-1 and NGAL) in the high-dose NGR_1 group decreased obviously and renal function indicators(BUN, Scr) improved significantly. The activity of SOD activity and expression level of GPX4 increased significantly in the high-dose NGR_1 group, whereas the expression level of MDA reduced and protein expression levels of Nrf2 and HO-1 increased. Simultaneously, HE staining of the renal tissue indicated that glomerular damage was greatly decreased in the high-dose NGR_1 group. In conclusion, this study has clarified that NGR_1 may alleviate the kidney injury of mice with IgAN by activating the Nrf2/HO-1 signaling pathway, improving antioxidant capacity, and reducing the level of renal oxidative stress.
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Glomerulonefrite por IGA , Camundongos , Animais , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Losartan/metabolismo , Losartan/farmacologia , Lipocalina-2/metabolismo , Lipocalina-2/farmacologia , Camundongos Endogâmicos C57BL , Rim/fisiologia , Transdução de Sinais , Estresse Oxidativo , Superóxido Dismutase/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Shen Shuai II Recipe (SSR) is a traditional Chinese medicine prescription with significant clinical efficacy in chronic kidney disease (CKD) by invigorating Qi and resolving blood stasis, clearing away heat and dampness. Our previous studies demonstrated that SSR attenuated renal interstitial fibrosis (RIF) by improving hypoxia and mitochondrial dysfunction. AIM OF THE STUDY: The aim of this study was to investigate the potential mechanisms of SSR against RIF. MATERIALS AND METHODS: The CKD was established by 5/6 ablation/infarction (A/I) operation. After 4 weeks, rats were gavaged with SSR or Fenofibrate for 8 weeks. Hypoxia-treated NRK-52 E cells were treated with SSR and (or) glycolysis inhibitors, including GSK2837808 A (GSK) and 2-Deoxy-D-glucose (2-DG). In addition, Drp1-deficient or MFP-M1-treated NRK-52 E cells were treated with SSR under hypoxic conditions. The effects of SSR on fibrotic phenotype, glycolysis, mitochondrial dynamics and membrane potential in hypoxia-exposed NRK-52 E cells were examined by immunoblotting, colorimetric, and fluorometric methods. Furthermore, we constructed a lactic acid-induced activation model of NRK-49 F cells and a co-culture system. The activation of NRK-49 F cells was evaluated by immunoblotting method. RESULTS: Our findings indicated that SSR significantly attenuated abnormal glycolysis in vivo and in vitro, which was correlated with its renoprotective effect. Further studies revealed that improvement of mitochondrial dynamics could be one of the mechanisms by which SSR inhibits glycolysis to achieve anti-renal fibrosis. Furthermore, treatment with SSR significantly inhibited the lactic acid-induced activation of NRK-49 F cells. The co-culture results further highlighted that SSR inhibited activation of renal fibroblasts and deposition of extracellular matrix by reducing glycolysis in renal tubular cells. CONCLUSIONS: SSR alleviates RIF by inhibiting hypoxia-induced glycolysis through improvement of mitochondrial dynamics.
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Nefropatias , Insuficiência Renal Crônica , Ratos , Animais , Dinâmica Mitocondrial , Nefropatias/tratamento farmacológico , Rim , Insuficiência Renal Crônica/tratamento farmacológico , Glicólise , Hipóxia/metabolismo , FibroseRESUMO
This study aims to explore the effect of icariin(ICA) on mitochondrial dynamics in a rat model of chronic renal failure(CRF) and to investigate the molecular mechanism of ICA against renal interstitial fibrosis(RIF). CRF was induced in male Sprague-Dawley(SD) rats with 5/6(ablation and infarction, A/I) surgery(right kidney ablation and 2/3 infarction of the left kidney). Four weeks after surgery, the model rats were randomized into the following groups: 5/6(A/I) group, 5/6(A/I)+low-dose ICA group, and 5/6(A/I)+high-dose ICA group. Another 12 rats that received sham operation were randomly classified into 2 groups: sham group and sham+ICAH group. Eight weeks after treatment, the expression of collagen-â (Col-â ), collagen-â ¢(Col-â ¢), mitochondrial dynamics-related proteins(p-Drp1 S616, p-Drp1 S637, Mfn1, Mfn2), and mitochondrial function-related proteins(TFAM, ATP6) in the remnant kidney tissues was detected by Western blot. The expression of α-smooth muscle actin(α-SMA) was examined by immunohistochemical(IHC) staining. The NRK-52 E cells, a rat proximal renal tubular epithelial cell line, were cultured in vitro and treated with ICA of different concentration. Cell viability was detected by CCK-8 assay. In NRK-52 E cells stimulated with 20 ng·mL~(-1) TGF-ß1 for 24 h, the effect of ICA on fibronectin(Fn), connective tissue growth factor(CTGF), p-Drp1 S616, p-Drp1 S637, Mfn1, Mfn2, TFAM, and ATP6 was detected by Western blot, and the ATP content and the mitochondrial morphology were determined. The 20 ng·mL~(-1) TGF-ß1-stimulated NRK-52 E cells were treated with or without 5 µmol·L~(-1) ICA+10 µmol·L~(-1) mitochondrial fusion promoter M1(MFP-M1) for 24 h and the expression of fibrosis markers Fn and CTGF was detected by Western blot. Western blot result showed that the levels of Col-â , Col-â ¢, and p-Drp1 S616 were increased and the levels of p-Drp1 S637, Mfn1, Mfn2, TFAM, and ATP6 were decreased in 5/6(A/I) group compared with those in the sham group. The levels of Col-â , Col-â ¢, and p-Drp1 S616 were significantly lower and the levels of p-Drp1 S637, Mfn1, Mfn2, TFAM, and ATP6 were significantly higher in ICA groups than that in 5/6(A/I) group. IHC staining demonstrated that for the expression of α-SMA in the renal interstitium was higher in the 5/6(A/I) group than in the sham group and that the expression in the ICA groups was significantly lower than that in the 5/6(A/I) group. Furthermore, the improvement in the fibrosis, mitochondrial dynamics, and mitochondrial function were particularly prominent in rats receiving the high dose of ICA. The in vitro experiment revealed that ICA dose-dependently inhibited the increase of Fn, CTGF, and p-Drp1 S616, increased p-Drp1 S637, Mfn1, Mfn2, TFAM, and ATP6, elevated ATP content, and improved mitochondrial morphology of NRK-52 E cells stimulated by TGF-ß1. ICA combined with MFP-M1 further down-regulated the expression of Fn and CTGF in NRK-52 E cells stimulated by TGF-ß1 compared with ICA alone. In conclusion, ICA attenuated RIF of CRF by improving mitochondrial dynamics.
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Falência Renal Crônica , Insuficiência Renal Crônica , Animais , Feminino , Masculino , Ratos , Trifosfato de Adenosina/farmacologia , Fibrose , Flavonoides , Infarto/metabolismo , Infarto/patologia , Rim , Dinâmica Mitocondrial , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: We aim to study the clinical effect of moxibustion at Laogong interval with Panax notoginseng on the short-term maturation and long-term patency of arteriovenous fistula. METHODS: Seventy-four pre-dialysis uremic patients who received distal forearm radial-cephalic fistula creations were enrolled in this study and randomly assigned to the control group and experimental group. After arteriovenous fistula creations, the control group underwent handgrip exercise, and the experimental group received moxibustion at Laogong acupoint interval with Panax notoginseng. Both groups received a 12-week treatment and were followed up for 24 weeks in all at the following time points: before creations and 2, 4, 8, 12, 24 weeks after creations. The diameter of anastomosis, the diameter and outflow of draining-veins 5 cm above anastomosis, the diameter and outflow of brachial arteries evaluated the maturation and patency of arteriovenous fistula. Enzyme linked immunosorbent assay determined serum levels of endothelin and nitric oxide. RESULTS: The maturity rate in the experimental group was significantly higher than that in the control group at 4 weeks after arteriovenous fistula creations (P = 0.048). The diameter of anastomosis, the diameter of draining veins, and the blood flow of draining veins increased in both groups during the whole 24 weeks. The diameter and blood flow of brachial arteries ascended in both groups during the previous 12 weeks. Compared with the control group, moxibustion at Laogong interval with Panax notoginseng significantly improved the value of the diameter of draining-veins (P = 0.016), the blood flow of draining-veins (P = 0.015), the diameter of brachial arteries (P < 0.001), and the blood flow of brachial arteries (P = 0. 012) at 2 weeks, and enhanced the blood flow of draining-veins (P = 0.029) and brachial arteries (P < 0.001) at 12 weeks. Serum levels of endothelin were significantly lower (P = 0.047), and serum levels of nitric oxide were markedly higher (P < 0.001) in the experimental group than that in the control group at 2 weeks after creations. CONCLUSIONS: Moxibustion at Laogong interval with Panax notoginseng was non-invasive and promoted the maturation of arteriovenous fistula at 4 weeks after creations. However, its long-term beneficial effect on patency at 24 weeks after creations was not significant. Trial registration Chinese Clinical Trial Registry, No. ChiCTR1900024042. Registered, http://www.chictr.org.cn/index.aspx.
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Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, are high likely co-administered in China. ZJP could significantly inhibit VEN pharmacokinetics in vitro and in rats through suppression of CYP2D6 activity. To date, however, no clinical study has demonstrated the clinical relevance. Here, the VEN pharmacokinetics at a single dose of VEN with or without co-administration of ZJP was compared. ZJP had a weak herb-drug interactions (HDI) on the pharmacokinetics of VEN. The geometric means of Cmax and AUC0-∞ of VEN increased by 36.7% and 34.6%, respectively, and the corresponding 90% confidence intervals (CIs) of geometric mean ratios (GMRs) exceed outside bioequivalent range of 0.80-1.25. However, the corresponding 90% CIs of GMRs of these parameters for ODV were within the range. Since ODV exposure (AUC), approximately 3.4-fold higher than that of VEN, hardly changed, the systemic exposure of VEN active moiety (VEN + ODV) with ZJP increased slightly (≤8.5%) compared with that of VEN alone. In addition, the incidence of VEN-related side effects, especially gastrointestinal relevance, was significantly reduced with ZJP. Therefore, rational concomitant use of VEN and ZJP might have low risk of HDI and be promising in clinical practice.
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Medicamentos de Ervas Chinesas , Animais , Antidepressivos , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Humanos , Ratos , Cloridrato de Venlafaxina/efeitos adversos , Cloridrato de Venlafaxina/farmacocinéticaRESUMO
BACKGROUND: Shen Shuai â ¡ Recipe (SSR) is an effective Chinese herbal formula for the treatment of patients with chronic kidney disease (CKD) in the clinic and significantly improves 5/6 ablation and infarction (A/I) surgery-induced renal interstitial fibrosis (RIF) and intrarenal hypoxia in rats. However, the underlying molecular mechanisms need further elucidation. PURPOSE: This study aims to investigate the renoprotective mechanisms of SSR in vivo and in vitro. METHODS: CKD model was induced in rats with 5/6 (A/I) surgery. 4 weeks later, rats were treated with vehicle or SSR or Fenofibrate by daily gavage. In vitro, HK2 cells exposed to hypoxia (1% O2) were treated with SSR in the presence or absence of 100 µM MitoTEMPO or 10 µM Mitochondrial Fusion Promoter M1. The effects of SSR on RIF, mitochondrial dynamics, oxidative metabolism, and mitochondrial ROS (mtROS) were determined by immunoblotting, colorimetric, and fluorometric assays according to the experimental protocols. Furthermore, to explore the mechanisms of SSR against RIF, HK2 cells of PGC-1α or MFN2 knockdown under hypoxic stimulation were treated with 400 µg/ml of SSR and (or) 1 µM of ZLN005. RESULTS: The results showed that treatment with SSR significantly improved mitochondrial morphology and function, up-regulated the expression of PGC-1α protein, and inhibited the production of mtROS in 5/6 (A/I) kidneys and hypoxia-treated HK2 cells, which may be closely correlated with its anti-RIF effect. In addition, compared to wild-type HK2 cells, the roles of SSR in improving mitochondrial dynamics and energy metabolism were greatly diminished in HK2 cells of PGC-1α knockdown under hypoxic exposure. More importantly, compared to ZLN005 or SSR combined with ZLN005 treatment, MFN2-deficient HK2 cells exhibited the increased protein levels of FN, α-SMA, TGF-ß1 and cleaved IL-1ß in response to hypoxic stimulation. CONCLUSION: SSR exerted the renoprotective effects by improving mitochondrial dynamics under hypoxic condition via PGC-1α activation.
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The clinical and experimental study into the effects of Chinese herbal medicines on chronic kidney disease has evolved over the past 40 years with new insight into their mechanism and evidence of their clinical effects. Among the many traditional Chinese herbs examined in chronic renal disease, five were found to have evidence of sufficient clinical efficacy, high frequency of use, and well-studied mechanism. They are: Abelmoschus manihot and Huangkui capsule, Salvia miltiorrhiza and its components (tanshinone II A, salvianolic acid A and B); Rhizoma coptidis and its monomer berberine; Tripterygium wilfordii and its components (triptolide, tripterygium glycosides); Kudzu root Pueraria and its monomer Puerarin. These Chinese herbal medications have pharmaceutical effects against fibrosis, inflammation and oxidative stress and also promote renal repair and regeneration. This article reviews their clinical efficacy, anti-fibrotic effects in animal models, and molecular mechanism of action.
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Icariin (ICA) is a bioactive flavonoid extracted from Epimedium brevicornum Maxim and exhibits a variety of pharmacological activities including antiinflammatory and antioxidant effects. Recently, icariin has shown renoprotective role by inhibiting pathological matrix. However, the underlying mechanisms of the efficacy remain unknown. This study aimed to determine the effects of icariin on renal fibrosis and explore its molecular mechanisms. Chronic kidney disease (CKD) was induced in rats with 5/6 ablation and infarction (A/I) operation. Four weeks later, rats were treated with vehicle or 20 mg/kg (low dose) or 40 mg/kg (high dose) of icariin by daily gavage. Furthermore, to further elucidate the effect mechanisms of icariin, in vitro, NRK-49F cells stimulated by 8 ng/ml IL-1ß were treated with icariin in the presence or absence of SB431542 or the neutralizing antibody of transforming growth factor-ß (TGF-ß) for 24 h. We showed that icariin treatment for 8 weeks dose-dependently improved 5/6 (A/I)-induced kidney injury and fibrosis, and blocked the release of inflammatory cytokine IL-1ß. In vitro, icariin inhibited IL-1ß/TGF-ß-mediated activation of renal fibroblasts. In summary, anti-fibrotic effects of icariin were interconnected with the inhibition of renal fibroblast activation caused by IL-1ß/TGF-ß signaling.
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Rim , Insuficiência Renal Crônica , Animais , Fibroblastos , Fibrose , Flavonoides/farmacologia , Interleucina-1beta , Rim/patologia , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Fatores de Crescimento TransformadoresRESUMO
BACKGROUND: Renal interstitial fibrosis is a pathological manifestation of progression of chronic kidney disease induced by various factors. Shen Shuai II Recipe (SSR) has been used in clinical practice for more than 20 years, and clinical studies have confirmed that SSR significantly improves the renal function of patients with chronic kidney disease. However, the specific mechanisms underlying its efficacy require further research. This study aims to explore the influencing factors of renal interstitial fibrosis in the context of hypoxia via the IL-1ß/c-Myc pathway and the potential molecular mechanisms of SSR intervention in vivo and in vitro. METHODS: A rat model of chronic renal failure was developed by performing 5/6 (ablation/infarction, A/I) surgery on randomly selected, male Sprague Dawley rats. Thirty-six successfully modeled rats were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + SSR, and 5/6 (A/I) + losartan. Another 12 rats were used as the sham group. After 8 weeks of the corresponding intervention, renal function, liver function, and protein expression of renal-fibrosis-related factors, HIF-1α, IL-1ß, and c-Myc, were detected. In vitro analysis was performed using hypoxia-induced rat renal tubular epithelial cells (NRK-52E) and IL-1ß-stimulated rat renal interstitial fibroblasts (NRK-49F). IL-1ß concentration in the culture medium and IL-1ß protein expression in hypoxic NRK-52E treated with different concentrations of SSR were investigated. Furthermore, we also studied the changes in protein expression of c-Myc and fibrosis-related factors after c-Myc gene silencing in IL-1ß-stimulated NRK-49F treated with SSR. RESULTS: Shen Shuai II Recipe significantly reduced RIF and downregulated the expression of HIF-1α, c-Myc, and IL-1ß proteins in 5/6 (A/I) rats with chronic renal failure. It also inhibited IL-1ß secretion from NRK-52E induced by hypoxia, which in turn inhibited fibroblast activation mediated by the IL-1ß/c-Myc pathway, and finally reduced the overproduction of the extracellular matrix. CONCLUSION: The renoprotective effects of SSR in rats with chronic renal failure may be related to its inhibition of hypoxia via the IL-1ß/c-Myc pathway. Thus, SSR is a potentially effective drug for delaying the progression of renal interstitial fibrosis.
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Emodin, a major component of Chinese herbal rhubarb, delays the progression of chronic renal failure. However, the effect and working mechanisms of Emodin on renal tubulointerstitial fibrosis remains elusive. We hypothesized that emodin inhibits renal tubulointerstitial fibrosis through EZH2, a histone methyltransferase. Our in vivo and in vitro studies demonstrate that emodin reduced extracellular collagen deposition and inhibited Smad3 and CTGF pro-fibrotic signaling pathways, which were correlated with the down-regulation of EZH2 and reduced trimethylation of histone H3 on lysine 27 (H3k27me3) in NRK-49F fibrotic cells and UUO kidneys. Inhibition of EZH2 by 3-DZNeP blocked or attenuated the anti-fibrotic effect of emodin in UUO kidneys and NRK-49F cells. These data indicate that emodin inhibits renal tubulointerstitial fibrosis in obstructed kidneys and this effect is mediated through EZH2.
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Emodina/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Fator de Crescimento do Tecido Conjuntivo/antagonistas & inibidores , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Inibidores Enzimáticos/farmacologia , Fibrose , Técnicas In Vitro , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/antagonistas & inibidores , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologiaRESUMO
BACKGROUND: Magnesium lithospermate B (MLB) can promote renal microcirculation. The aim of the current project was to study whether MLB improves renal hemodynamics, oxygen consumption and subsequently attenuates hypoxia in rats induced by 5/6th renal Ablation/Infarction(A/I). METHODS: Chronic renal failure (CRF) was induced in male SD rats by the 5/6 (A/I) surgery. 30 rats were randomly divided into three groups: sham group, 5/6 (A/I) + vehicle group (CRF group) and 5/6 (A/I) + MLB (CRF + MLB) group. 28 days after the surgery, rats were given with saline or 100 mg/kg MLB by i.p. injection for 8 weeks. The 24-h urinary protein (24hUp), serum creatinine (Scr), blood urine nitrogen (BUN), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. The protein expression of Fibronectin (FN), Collagen-I (Col-I), Connective Tissue Growth Factor(CTGF) and Interleukin-6 (IL-6) were measured by Western blot. Renal blood flow (RBF) and renal O2 consumption (QO2) indicated as sodium reabsorption (QO2/TNa) were detected before sacrifice. Renal hypoxia was assessed by measuring the protein expression of nNOS, HIF-1α and VEGF. RESULTS: MLB significantly reduced 24hUp, Scr, BUN, SBP and DBP levels in rats with CRF. The expression of FN, Col-I, CTGF and IL-6 were down-regulated by MLB treatment in rats with CRF. In comparison to sham operated rats, 5/6 (A/I) rats had significantly lower RBF, and MLB significantly increased RBF in rats with CRF. Moreover, QO2/TNa was higher in the CRF group as compared to that in the sham group, and it was significantly attenuated in the CRF + MLB group. MLB reversed the expression of nNOS (neuronal nitric oxide synthase), HIF-1α (hypoxia inducible factor-1) and VEGF in rats with CRF. CONCLUSIONS: MLB improves renal function, fibrosis and inflammation in CRF rats induced by 5/6 (A/I), which is probably related to the increase in RBF, reduction of oxygen consumption and attenuation of renal hypoxia in the remnant kidney with CRF.