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Purpose: The number of clinical reports of acupuncture therapy in chronic kidney disease (CKD) is gradually increasing. This systematic review and meta-analysis aim to examine the therapeutic role of acupuncture therapy in kidney function and common symptoms in CKD patients.Methods: We searched Embase, PubMed, Scopus, Web of Science, China National Knowledge Infrastructure, WanFang, and WeiPu for randomized controlled trials comparing acupuncture treatment with control or placebo groups. We assessed the effect of acupuncture therapy in CKD patients using a meta-analysis with the hartung-knapp-sidik-jonkman random effects model. In addition, we visualized keyword co-occurrence overlay visualization with the help of VOSviewer software to describe the research hotspots of acupuncture therapy and CKD.Results: A total of 24 studies involving 1494 participants were included. Compared to the control group, acupuncture therapy reduced serum creatinine levels (standardized mean difference [SMD]: -0.57; 95% CI -1.05 to -0.09) and relieved pruritus (SMD: -2.20; 95% CI -3.84, -0.57) in patients with CKD, while the TSA showed that the included sample size did not exceed the required information size. The included studies did not report acupuncture-related adverse events.Conclusions: Acupuncture is an effective and safe treatment for improving kidney function and relieving pruritic symptoms in patients with CKD, but the very low evidence may limit this conclusion. The TSA suggests that high-quality trials are needed to validate the efficacy of acupuncture therapy.
Acupuncture therapy may improve kidney function and relieve pruritus symptoms in CKD patients, but both are very low evidence.Trial sequential analysis shows insufficient evidence for acupuncture therapy in CKD patients.Future research could focus on the role of acupuncture for functional capacity, insomnia, and pain in CKD patients.
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Terapia por Acupuntura , Insuficiência Renal Crônica , Humanos , China , Prurido , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , RimRESUMO
Recent studies have shown that the combined use of renin angiotensin system inhibitor, SGLT2 inhibitors and/or mineralocorticoid receptor antagonist provides additional renal protection for patients with diabetic kidney disease (DKD). Similarly, in traditional Chinese medicine, the synergistic application of multiple herbs often brings more significant therapeutic effects. However, the synergistic or additive mechanisms of traditional Chinese medicine in combination therapy are not fully understood. In our previous studies, we show that arctigenin (ATG), a major component of Fructus Arctii, attenuates proteinuria and renal injury in diabetic mice by activating PP2A, and puerarin (a class of known isoflavones) can also reduce proteinuria and renal injury in diabetic mice via activation of Sirt1. Here, we further explored the potential additive renal protection of these two compounds in diabetic mice. Research has found that ATG and puerarin have a synergistic effect in reducing albuminuria in db/db mice. Mechanistically, we found that ATG reduced NF-κB p65 phosphorylation likely through activation of PP2A while puerarin reduced p65 acetylation via Sirt1 activation. Therefore, ATG and puerarin have additive inhibitory effects on the NF-κB activation, which is a key inflammatory pathway in DKD. RNA-sequencing analysis revealed distinct pathways activated by ATG and puerarin in the diabetic kidney, which may provide an additional mechanism for their additive effects in DKD. Our study suggests that ATG and puerarin could be a new combination therapy for DKD and reveals its underlined mechanisms.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Furanos , Isoflavonas , Lignanas , Humanos , Camundongos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Sirtuína 1/metabolismo , NF-kappa B/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Rim , Isoflavonas/farmacologia , Proteinúria/metabolismoRESUMO
Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut-renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.
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Microbioma Gastrointestinal , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Camundongos , Glutamina , Apoptose , FibroseRESUMO
OBJECTIVE: To observe the effects of electroacupuncture (EA) on renal fibrosis, the expression of transforming growth factor-ß1 (TGF-ß1) and epithelial mesenchymal transition (EMT) marker proteins in renal tissue of spontaneously hypertensive rats (SHR), so as to explore the underlying mechanism on EA alleviating hypertensive renal impairment. METHODS: Twenty-four male SHR were randomly divided into model group, losartan group and EA group, with 8 rats in each group, and eight male Wistar-Kyoto rats were taken as the normal group. Rats in the losartan group received gavage of losartan potassium solution (3 mg/mL, 30 mg·kg-1·d-1),once every other day for 12 weeks. Rats in the EA group received EA stimulation at bilateral "Shenshu" (BL23) and "Geshu" (BL17) (2 Hz/15 Hz, 1.0 mA), 15 min each time, once every other day for 12 weeks. The systolic blood pressure of caudal artery was measured before, and 4, 8 and 12 weeks after the intervention. The 24-hour urinary protein was measured before, and 6 and 12 weeks after the intervention. Histopathological changes of the left renal tissue were observed under light mircoscope after H.E. stain. Extracellular matrix (ECM) in renal tissues was observed after periodate Schiff staining. Basement membrane and collagen fibers were observed after Masson staining with collagen volume fraction (CVF) evaluated. The expression of TGF-ß1 mRNA in the right renal was detected by real-time fluorescence quantitative PCR. The expression of TGF-ß1 and EMT marker E-cadherin, α-SMA and fibronectin (FN) proteins in the left renal tissue was measured by immunohistochemistry. RESULTS: In the model group, irregular arrangement of nephrocytes, renal tubule atrophy, lumen stenosis, ECM hyperplasia and deposition, scar and sclerosis were observed, which were relatively milder in the EA and losartan groups. Compared with the normal group, tubulointerstitium CVF, systolic blood pressure of caudal artery before, and at 4, 8 and 12 weeks after the intervention, 24-hour urinary protein before, and at 6 and 12 weeks after the intervention, the expression of TGF-ß1 mRNA, area of TGF-ß1, α-SMA and FN positive staining in renal tissues were significantly increased (P<0.01), while the area of E-cadherin positive staining was significantly decreased (P<0.01) in the model group. Compared with the model group, tubulointerstitium CVF, systolic blood pressure of caudal artery at 4, 8 and 12 weeks after the intervention, 24-hour urinary protein at 6 and 12 weeks after the intervention, the expression of TGF-ß1 mRNA, area of TGF-ß1, α-SMA and FN positive staining in renal tissues were significantly decreased (P<0.01ï¼P<0.05), while area of E-cadherin positive staining was significantly increased (P<0.01) in the losartan and EA groups. Compared with the losartan group, the area of E-cadherin was conside-rately increased (P<0.01), while the area of α-SMA protein decreased (P<0.01) in the EA group. CONCLUSION: EA could effectively alleviate hypertension and renal interstitial fibrosis in SHR, the mechanism of which may be related to its function in reducing the expression of TGF-ß1 and inhibiting EMT in renal tissue.
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Eletroacupuntura , Hipertensão , Masculino , Ratos , Animais , Ratos Endogâmicos WKY , Ratos Endogâmicos SHR , Fator de Crescimento Transformador beta1 , Transição Epitelial-Mesenquimal , Losartan , CaderinasRESUMO
Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves podocyte injury in type 1 DKD mice. However, the direct molecular target of puerarin and its underlying mechanisms in DKD remain unknown. In this study, we confirmed that puerarin also improved DKD in type 2 diabetic db/db mice. Through RNA-sequencing odf isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability method combined with mass spectrometry analysis, we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and mouse diabetic kidney in vivo. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. Inhibition of PKA by Rp-cAMP also diminished the effects of puerarin on high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Podócitos , Animais , Apoptose , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/farmacologia , Glucose/metabolismo , Guanidina/metabolismo , Guanidina/farmacologia , Guanidina/uso terapêutico , Humanos , Isoflavonas , Camundongos , Nucleotídeos/metabolismo , Podócitos/metabolismoRESUMO
In this study, we developed a radial artery pulse acquisition system based on finger-worn dense pressure sensor arrays to enable three-dimensional pulse signals acquisition. The finger-worn dense pressure-sensor arrays were fabricated by packaging 18 ultra-small MEMS pressure sensors (0.4 mm × 0.4 mm × 0.2 mm each) with a pitch of 0.65 mm on flexible printed circuit boards. Pulse signals are measured and recorded simultaneously when traditional Chinese medicine practitioners wear the arrays on the fingers while palpating the radial pulse. Given that the pitches are much smaller than the diameter of the human radial artery, three-dimensional pulse envelope images can be measured with the system, as can the width and the dynamic width of the pulse signals. Furthermore, the array has an effective span of 11.6 mm-3-5 times the diameter of the radial artery-which enables easy and accurate positioning of the sensor array on the radial artery. This study also outlines proposed methods for measuring the pulse width and dynamic pulse width. The dynamic pulse widths of three volunteers were measured, and the dynamic pulse width measurements were consistent with those obtained by color Doppler ultrasound. The pulse wave velocity can also be measured with the system by measuring the pulse transit time between the pulse signals at the brachial and radial arteries using the finger-worn sensor arrays.
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Puerarin, an active compound of radix puerariae, is a major compound used in Chinese herbal medicines to treat patients with diabetic nephropathy (DN). In the previous studies, we showed that puerarin exerts renoprotective effects in Streptozocin (STZ)-induced diabetic mice through activation of Sirt1 and anti-oxidative effects. Here, we further investigated the underlying mechanism mediating the renal protective effects of puerarin in DN. We studied the effects and mechanism of puerarin in STZ-induced diabetic mice and in cultured immortalized mouse podocytes treated with high glucose. We confirmed that puerarin ameliorated urinary albumin creatinine ratio and kidney injury in STZ-induced DN mice. We found that expression of heme oxygenase 1 (HMOX-1) and Sirt1 was suppressed in diabetic glomeruli but restored by puerarin treatment at both mRNA and protein levels. Additionally, we found that puerarin induced autophagy in the kidney of DN mice. In conditionally immortalized mouse podocytes, puerarin inhibited HG-induced apoptosis and restored the mRNA and protein levels of HMOX-1 and Sirt1. Interestingly, we showed that puerarin decreased liver kinase B1 (LKB1) acetylation, thereby promoting adenosine 5'-monophosphate-activated protein kinase-dependent autophagy. Knockdown of HMOX-1 and Sirt1 expression or treatment with the autophagy inhibitor 3-methyladenine abolished the protective effects of puerarin in HG-treated podocytes. Taken together, these results suggest that puerarin protects podocytes from diabetes-induced injury through HMOX1 and Sirt1-mediated upregulation of autophagy, a novel mechanism explaining its renal protective effects in DN.
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Diabetic kidney disease (DKD) is the most common microvascular complication of diabetes and is one of the main causes of end-stage renal disease (ESRD) in many countries. The pathological features of DKD are the hypertrophy of mesangial cells, apoptosis of podocytes, glomerular basement membrane (GBM) thickening, accumulation of extracellular matrix (ECM), glomerular sclerosis, and tubulointerstitial fibrosis. The etiology of DKD is very complicated and many factors are involved, such as genetic factors, hyperglycemia, hypertension, hyperlipidemia, abnormalities of renal hemodynamics, and metabolism of vasoactive substances. Although some achievements have been made in the exploration of the pathogenesis of DKD, the currently available clinical treatment methods are still not completely effective in preventing the progress of DKD to ESRD. CHM composed of natural products has traditionally been used for symptom relief, which may offer new insights into therapeutic development of DKD. We will summarize the progress of Chinese herbal medicine (CHM) in the treatment of DKD from two aspects. In clinical trials, the Chinese herbal formulas were efficacy and safety confirmed by the randomized controlled trials. In terms of experimental research, studies provided evidence for the efficacy of CHM from the perspectives of balancing metabolic disorders, reducing inflammatory response and oxidative stress, antifibrosis, protecting renal innate cells, and regulating microRNA and metabolism. CHM consisting of different ingredients may play a role in synergistic interactions and multiple target points in the treatment of DKD.
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Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Nefropatias Diabéticas/patologia , Medicamentos de Ervas Chinesas/farmacologia , Fibrose/patologia , Humanos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Podócitos/patologia , Resultado do TratamentoRESUMO
Multiple studies have demonstrated a critical role of Sirtuin-1 (SIRT1) deacetylase in protecting kidney cells from cellular stresses. A protective role of SIRT1 has been reported in both podocytes and renal tubular cells in multiple kidney disease settings, including diabetic kidney disease (DKD). We and others have shown that SIRT1 exerts renoprotective effects in DKD in part through the deacetylation of transcription factors involved in the disease pathogenesis, such as p53, FOXO, RelA/p65NF-κB, STAT3, and PGC1α/PPARγ. Recently we showed that the podocyte-specific overexpression of SIRT1 attenuated proteinuria and kidney injury in an experimental model of DKD, further confirming SIRT1 as a potential target to treat kidney disease. Known agonists of SIRT1 such as resveratrol diminished diabetic kidney injury in several animal models. Similarly, we also showed that puerarin, a Chinese herbal medicine compound, activates SIRT1 to provide renoprotection in mouse models of DKD. However, as these are non-specific SIRT1 agonists, we recently developed a more specific and potent SIRT1 agonist (BF175) that significantly attenuated diabetic kidney injury in type 1 diabetic OVE26 mice. We also previously reported that MS417, a bromodomain inhibitor that disrupts the interaction between the acetyl-residues of NF-κB and bromodomain-containing protein 4 (BRD4) also attenuates DKD. These results suggest that SIRT1 agonists and bromodomain inhibitors could be potential new therapuetic treatments against DKD progression.
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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.
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Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Isoflavonas/farmacologia , NADPH Oxidase 4/metabolismo , Podócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Albuminúria/tratamento farmacológico , Albuminúria/enzimologia , Albuminúria/patologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/patologia , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/deficiência , Óxido Nítrico Sintase Tipo III/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Podócitos/enzimologia , Podócitos/patologia , RNA Mensageiro/metabolismo , Sirtuína 1/metabolismo , Superóxidos/metabolismoRESUMO
The patient's response to drug treatment is usually systems-wide based on multi-spots through either direct or indirect targets. Thus, the evaluation of the treatment cannot rely on single targeted biomarker, especially for complex diseases such as chronic kidney disease. In the present study, we performed a systems-wide analysis using proteomic approach to quantify changes in the proteomic profiles of the plasma from IgA nephropathy (IgAN) patients before and after treatment. In particular, the patient-to-health distances based on global proteome quantification before and after treatment were calculated and considered as quantitative readouts to measure patient divergences from the healthy condition. We found that the patient-to-health distance nicely correlated with the patient's response to drug treatment and long-term prognosis, which created a self-tracking platform for personalized evaluation. In addition, the steroid treatment plays a role in immunosuppression, while the Chinese Traditional Medicine (TCM) can modulate whole-body systems. Our results indicated that STC therapy normalized the proteomic profile more significantly than SA therapy. This work provides an omics-based and systematic platform for personalized evaluation of disease treatment. This strategy could help us to evaluate treatment outcomes and predict prognosis in patients with IgAN and other complex diseases.
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Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/tratamento farmacológico , Medicina de Precisão/métodos , Proteômica/métodos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Esteroides/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Masculino , Medicina Tradicional Chinesa/efeitos adversos , Medicina de Precisão/efeitos adversos , Proteoma/análise , Proteoma/efeitos dos fármacos , Proteoma/metabolismo , Resultado do TratamentoRESUMO
Because current treatment options for chronic kidney disease (CKD) are limited, many patients seek out alternative therapies such as traditional Chinese medicine. However, there is a lack of evidence from large clinical trials to support the use of traditional medicines in patients with CKD. Many active components of traditional medicine formulas are undetermined and their toxicities are unknown. Therefore, there is a need for research to identify active compounds from traditional medicines and understand the mechanisms of action of these compounds, as well as their potential toxicity, and subsequently perform well-designed, randomized, controlled, clinical trials to study the efficacy and safety of their use in patients with CKD. Significant progress has been made in this field within the last several years. Many active compounds have been identified by applying sophisticated techniques such as mass spectrometry, and more mechanistic studies of these compounds have been performed using both in vitro and in vivo models. In addition, several well-designed, large, randomized, clinical trials have recently been published. We summarize these recent advances in the field of traditional medicines as they apply to CKD. In addition, current barriers for further research are also discussed. Due to the ongoing research in this field, we believe that stronger evidence to support the use of traditional medicines for CKD will emerge in the near future.
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Medicamentos de Ervas Chinesas/uso terapêutico , Nefropatias/terapia , Medicina Tradicional Chinesa , Medicamentos de Ervas Chinesas/farmacologia , Fibrose , Humanos , Imunomodulação , Inflamação/tratamento farmacológico , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Estresse Oxidativo/efeitos dos fármacos , Resultado do TratamentoRESUMO
Nephrokeli (NPKL) is a Chinese herbal formula that has been used to treat patients with IgA nephropathy (IgAN) for improvement of proteinuria and kidney injury. However, the mechanism remains unclear. Sphingosine-1-phosphate (S1P) and its receptors S1PR2 and S1PR3 are known to play an important role in kidney disease. Here, we tested whether NPKL is able to regulate the S1P pathway in the kidney of IgAN rats. Four groups of rats were included in the study: Control, IgAN, IgAN treated with losartan, and IgAN treated with NPKL. The IgAN model was generated by injection of bovine serum albumin and staphylococcus enterotoxin B. We found that IgAN rats had increased staining for proliferating cell nuclear antigen (PCNA) in the mesangial area and increased mRNA and protein levels of S1PR2 and S1PR3 in the kidney compared to control rats. Connective tissue growth factor (CTGF), a downstream growth factor in the S1P pathway, was also elevated in the kidney of IgAN rats. Treatment with either NPKL or losartan was able to reduce PCNA staining and the expression of both S1PR2 and S1PR3 in the kidney of IgAN rats. However, NPKL (but not losartan treatment) reduced the expression of CTGF in the kidney of IgAN rats. In addition, we treated rat mesangial cells with sera collected from either NPKL-treated rats or control rats and found that NPKL-serum was able to reduce S1P-induced mesangial cell proliferation and the expression of S1PR2/S1PR3 and CTGF. NPKL also attenuates expression of fibrosis, inflammation, and oxidative stress markers in the kidney of IgAN rats. Our studies provide the mechanism by which NPKL attenuates kidney injury in IgAN rats.
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Medicamentos de Ervas Chinesas/uso terapêutico , Glomerulonefrite por IGA/tratamento farmacológico , Rim/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Rim/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/metabolismo , Receptores de Esfingosina-1-FosfatoRESUMO
Radix puerariae, a traditional Chinese herbal medication, has been used successfully to treat patients with early stage of diabetic nephropathy. However, the underlined mechanism of this renal protective effect has not been determined. In the current study, we investigated the effects and the mechanism of puerarin in Streptozotocin (STZ)-induced diabetic rats. We treated STZ-rats with either puerarin or losartan, an angiotensin II receptor blocker, as compared to those treated with vehicle. We found that both puerarin and losartan attenuated kidney hypertrophy, mesangial expansion, proteinuria, and podocyte foot process effacement in STZ rats. In addition, both puerarin and losartan increased expression of podocyte slit diaphragm proteins such as nephrin and podocin. Interestingly, we found that puerarin treatment induced a more pronounced suppression of oxidative stress production and S-nitrosylation of proteins in the diabetic kidneys as compared to losartan treatment. Furthermore, we found that matrix metalloproteinase-9 (MMP-9), which is known to be activated by oxidative stress and S-nitrosylation of proteins, was also suppressed more extensively by puerarin than losartan. In conclusion, these data provide for the first time the potential mechanism to support the use of puerarin in the treatment of early diabetic nephropathy.
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Diabetes Mellitus Experimental/enzimologia , Nefropatias Diabéticas/enzimologia , Isoflavonas/farmacologia , Metaloproteinase 9 da Matriz/genética , Animais , Colágeno Tipo IV/metabolismo , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Avaliação Pré-Clínica de Medicamentos , Repressão Enzimática , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isoflavonas/uso terapêutico , Rim/efeitos dos fármacos , Rim/enzimologia , Losartan/farmacologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Podócitos/efeitos dos fármacos , Proteinúria/prevenção & controle , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , EstreptozocinaRESUMO
Traditional Chinese herbal medications (TCHMs) are frequently used in conjunction with western pharmacotherapy for treatment of chronic kidney diseases (CKD) in China and many other Asian countries. The practice of traditional Chinese medicine is guided by cumulative empiric experience. Recent in vitro and animal studies have confirmed the biological activity and therapeutic effects of several TCHMs in CKD. However, the level of evidence supporting TCHMs is limited to small, nonrandomized trials. Due to variations in the prescription pattern of TCHMs and the need for frequent dosage adjustment, which are inherent to the practice of traditional Chinese medicine, it has been challenging to design and implement large randomized clinical trials of TCHMs. Several TCHMs are associated with significant adverse effects, including nephrotoxicity. However, reporting of adverse effects associated with TCHMs has been inadequate. To fully realize the therapeutic use of TCHMs in CKD, we need molecular studies to identify active ingredients of TCHMs and their mechanism of action, rigorous pharmacologic studies to determine the safety and meet regulatory standards required for clinical therapeutic agents, and well-designed clinical trials to provide evidence-based support of their safety and efficacy.
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Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Medicina Tradicional Chinesa , Insuficiência Renal Crônica/diagnóstico , Resultado do TratamentoRESUMO
BACKGROUND: To compare the safety and efficacy of the traditional Chinese medicine Shenqi particle and standard therapy with prednisone and cyclophosphamide (control) in adult patients with idiopathic membranous nephropathy (IMN). STUDY DESIGN: Open-label, multicenter, parallel, randomized, controlled clinical trial. SETTING & PARTICIPANTS: From April 2008 to February 2011, a total of 190 patients with biopsy-proven IMN from 7 hospitals in China participated in the study. All patients had nephrotic syndrome with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2). INTERVENTION: Shenqi particle (9.6 g 3 times per day) or prednisone (1 mg/kg/d tapering to 0.17 mg/kg/d) and cyclophosphamide (total dose of 9-12 g per square meter of body surface area) for 48 weeks. OUTCOMES: Primary outcomes included complete remission, defined as proteinuria (24-hour urine protein excretion) ≤0.3 g/d, or partial remission, defined as proteinuria with protein excretion >0.3-<3.5 g/d and a 50% reduction from its peak value at 48 weeks. Secondary outcomes included serum albumin level, eGFR, doubling of serum creatinine level, end-stage renal disease, and death. RESULTS: Baseline values for proteinuria and eGFR were 5.34 ± 2.74 g/d and 84.0 ± 27.4 mL/min/1.73 m(2) for the Shenqi particle group and 5.33 ± 2.47 g/d and 83.8 ± 24.9 mL/min/1.73 m(2) for the control group, respectively. 132 patients (63 Shenqi particle group, 69 control group) completed the study. Change in urinary protein excretion in the Shenqi particle group was -3.01 (95% CI, -3.68 to -2.34) g/d, and in the control group, -3.28 (95% CI, -3.98 to -2.58) g/d; the mean difference between groups was 0.27 (95% CI, -0.70 to 1.23) g/d (P = 0.6). Changes in eGFR were 12.3 (95% CI, 4.99 to 19.6) mL/min/1.73 m(2) in the Shenqi particle group and -2.8 (95% CI, -10.32 to 4.77) mL/min/1.73 m(2) in the control group; the mean difference between groups was 15.1 (95% CI, 4.56 to 25.55) mL/min/1.73 m(2) (P = 0.005). Severe adverse events occurred in only the control group (14.5%) and included lung infection, liver injury, and pneumonia. LIMITATIONS: High rate of loss to follow-up and lack of observation period prior to the study. CONCLUSIONS: Shenqi particle may be a promising alternative therapy for adults with IMN and nephrotic syndrome.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Fitoterapia , Extratos Vegetais/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Biópsia , China , Ciclofosfamida/uso terapêutico , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Rim/patologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/patologia , Extratos Vegetais/efeitos adversos , Prednisona/uso terapêuticoRESUMO
Membranous nephropathy (MN) is the most common cause of idiopathic nephrotic syndrome in adults and the cause is known to be due to the injury of podocytes located in the glomeruli. Astragalus membranaceus has been used for the treatment of patients with MN in China for a long time. The beneficial effect of Astragalus membranaceus on proteinuria of patients with MN has been well documented. However, the mechanism of astragalus membranaceu in alleviation of MN is still not completely understood. Therefore, in the current study, we employed a podocyte injury model induced by complement membranous attack complex to examine the mechanism of astragalus membraneceus in the treatment of MN. We found that complement membranous attack complex could increase lactate dehydrogenase (LDH) release from podocytes and astragaloside IV (AS-IV) could prevent LDH release from podocytes in a time- and dose-dependent pattern. Moreover, AS-IV restored podocyte morphology and cytoskeleton loss induced by complement membranous attack complex. Furthermore, AS-IV was able to reduce phosphorylation of JNK and ERK1/2 induced by complement membranous attack complex. In conclusion, the mechanism of Astragalus membranaceus in the treatment of MN may be related to its attenuation of podocyte injury through regulation of cytoskeleton and mitogen activated protein kinase.
Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Sistema de Sinalização das MAP Quinases , Podócitos/patologia , Saponinas/farmacologia , Triterpenos/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Animais , Astragalus propinquus/química , Linhagem Celular , Citoproteção , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Glomerulonefrite Membranosa/patologia , Imuno-Histoquímica , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Camundongos , Fosforilação , Podócitos/efeitos dos fármacos , Podócitos/enzimologia , Substâncias Protetoras/farmacologia , Proteinúria/patologia , Fatores de TempoRESUMO
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is a growing public health problem with an urgent need for new pharmacological agents. Cordyceps cicadae is widely used in traditional Chinese medicine (TCM) and has potential renoprotective benefits. The current study aimed to determine any scientific evidence to support its clinical use. METHODS: We analyzed the potential of two kinds of C. cicadae extract, total extract (TE) and acetic ether extract (AE), in treating kidney disease simulated by a subtotal nephrectomy (SNx) model. Sprague-Dawley rats were divided randomly into seven groups: sham-operated group, vehicle-treated SNx, Cozaar, 2 g/(kgâd) TE SNx, 1 g/(kgâd) TE SNx, 92 mg/(kgâd) AE SNx, and 46 mg/(kgâd) AE SNx. Renal injury was monitored using urine and serum analyses, and hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) stainings were used to analyze the level of fibrosis. The expression of type IV collagen (Col IV), fibronectin (FN), transforming growth factor-ß1 (TGF-ß1), and connective tissue growth factor (CTGF) was detected by immunohistochemistry. RESULTS: Renal injury, reflected in urine and serum analyses, and pathological changes induced by SNx were attenuated by TE and AE intervention. The depositions of Col IV and FN were also decreased by the treatments and were accompanied by reduced expression of TGF-ß1 and CTGF. In some respects, 2 g/(kgâd) of TE produced better effects than Cozaar. CONCLUSIONS: For the first time, we have shown that C. cicadae may inhibit renal fibrosis in vivo through the TGF-ß1/CTGF pathway. Therefore, we conclude that the use of C. cicadae could provide a rational strategy for combating renal fibrosis.
Assuntos
Cordyceps/química , Falência Renal Crônica/microbiologia , Falência Renal Crônica/terapia , Medicina Tradicional Chinesa/métodos , Extratos Vegetais/uso terapêutico , Insuficiência Renal/microbiologia , Insuficiência Renal/terapia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
OBJECTIVE: To observe the correlation between traditional Chinese medicine (TCM) syndromes ("deficiency of qi and yin" and "deficiency of liver yin and kidney yin") and A267G in 5'-untranslated region within exonal of megsin gene, and to search the substantial genetic basis for micro-differentiation of TCM syndromes in primary immunoglobulin A nephropathy (IgAN). METHODS: A total of 120 IgAN cases meeting the diagnostic criteria were enrolled. The sequence of single nucleotide polymorphism (SNP) of A267G in 5'-untranslated region within exonal of megsin gene was tested. The correlation between SNP and TCM syndromes was observed. RESULTS: There were 83 cases carrying GG genotype, 34 cases carrying GA genotype and 3 cases carrying AA genotype in 120 cases of primary IgAN. There was a high proportion of "deficiency of liver yin and kidney yin" in IgAN cases with AA and GA genotypes, and a high proportion of "deficiency of qi and yin" in IgAN cases with GG genotype (P<0.01). Odds ratio in TCM syndrome distribution between GG genotype and GA plus AA genotype was 9.800, and 95% confidence interval was 3.969-24.199. The discrepancy also resided in IgAN patients with different genders and ages. CONCLUSION: A267G in 5'-untranslated region within exonal of the megsin gene may be one of the substantial genetic basis for differentiating "deficiency of liver yin and kidney yin" syndrome and "deficiency of qi and yin" syndrome in primary IgAN.