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1.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201387

RESUMO

Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK1, oxalate could induce cell damage in a time- and dose-dependent manner; this was associated with increased arachidonate 12-lipoxygenase (ALOX12) expression and synthesis of endovanilloid 12(S)-hydroxyeicosatetraenoic acid for TRPV1 activation. Inhibition of ALOX12 or TRPV1 attenuated oxalate-mediated cell damage. We further showed that increases in intracellular Ca2+ and protein kinase C α activation are downstream of TRPV1 for NADPH oxidase 4 upregulation and reactive oxygen species formation. These trigger tubular cell inflammation via increased NLR family pyrin domain-containing 3 expression, caspase-1 activation, and interleukin (IL)-1ß release, and were alleviated by TRPV1 inhibition. Male hyperoxaluric rats demonstrated urinary supersaturation, tubular damage, and oxidative stress in a time-dependent manner. Chronic TRPV1 inhibition did not affect hyperoxaluria and urinary supersaturation, but markedly reduced tubular damage and calcium oxalate crystal deposition by lowering oxidative stress and inflammatory signaling. Taking all these results together, we conclude that TRPV1 hyperfunction contributes to oxalate-induced renal inflammation. Blunting TRPV1 function attenuates hyperoxaluric nephropathy.


Assuntos
Injúria Renal Aguda/complicações , Hiperoxalúria/complicações , Inflamação/patologia , Nefrite/patologia , Oxalatos/toxicidade , Estresse Oxidativo , Canais de Cátion TRPV/metabolismo , Animais , Hiperoxalúria/induzido quimicamente , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Nefrite/etiologia , Nefrite/metabolismo , Ratos , Ratos Wistar , Canais de Cátion TRPV/genética
2.
Medicine (Baltimore) ; 100(19): e25852, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106629

RESUMO

BACKGROUND: In recent years, the incidence rate of hypertensive nephropathy has been increasing quickly, which has been a major threat to people's health. Renin-angiotensin-aldosterone system blockers have certain curative effects. However, there are some patients having serious adverse reactions, and the benefit population is limited, so the treatment of hypertensive renal damage is necessary to have beneficial supplement. More and more clinical studies have shown that ginkgo leaf extract and dipyridamole injection (GDI) combined with antihypertensive drugs has achieved good results in the treatment of hypertensive renal damage. It is supposed to be a supplementary treatment in hypertensive nephropathy. OBJECTIVES: To systematically assess the efficacy and safety of GDI combined with antihypertensive drugs on hypertensive renal injury. METHODS: Seven databases including PubMed, Cochrane Library, Embase, Wanfang database, China biomedical literature service system (Sino Med), VIP Chinese Sci-tech journal database (VIP), and China national knowledge internet (CNKI) were retrieved to collect randomized controlled trials (RCTs) in the experimental group containing combined therapy of hypertensive nephropathy with GDI and antihypertensive drugs. The retrieval time was from the establishment of database to July 8, 2020. Two researchers independently selected literature, extracted data, and evaluated the risk of bias in the study. The methodological quality was evaluated with Cochrane handbook and meta-analysis was performed with Stata 14.0 software. RESULTS: Eight studies were included in this study which involved 556 patients. The meta-analyses indicated that, compared with using antihypertensive drugs alone, combined treatment of GDI with antihypertensive drugs can decrease 24-hour urinary total protein (weighted mean difference [WMD] -0.61, 95% confidence interval [CI]: -0.82, -0.39; k = 6, P ≤ .001), blood urea nitrogen (WMD -1.27, 95% CI: -2.45, -0.10; k = 6, P = .033, serum creatinine (WMD -29.50, 95% CI: -56.44, -2.56; number of estimates [k] = 6, P = .032). CONCLUSIONS: Our meta-analyses showed that GDI combined with antihypertensive drugs can improve the renal function of hypertensive patients with renal injury.


Assuntos
Anti-Hipertensivos/uso terapêutico , Dipiridamol/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão Renal/tratamento farmacológico , Nefrite/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Vasodilatadores/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Dipiridamol/administração & dosagem , Dipiridamol/efeitos adversos , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Testes Hematológicos , Humanos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Urinálise , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos
3.
Life Sci ; 279: 119661, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087282

RESUMO

AIMS: Adaptor protein p66Shc, encoded by Shc1 gene, contributes to the pathogenesis of oxidative stress-related diseases. p66Shc ability to promote oxidative stress-related diseases requires phosphorylation of serine 36 residue (Ser36) and depends on translocation of p66Shc to the mitochondria. We tested the hypothesis that abnormal p66Shc-mediated reactive oxygen species (ROS) production could be critically involved in nephrons development during nephrogenesis. MAIN METHODS: We have generated unique mutant rats (termed p66Shc-Del), which express endogenous p66Shc with a 9-amino acid deletion, and lack regulatory Ser36. H2O2 renal production was measured by enzymatic microelectrode biosensors. Nephron numbers in 3-5 weeks old p66Shc-Del rats were quantified using the acid maceration method. KEY FINDINGS: p66Shc-Del rats, as wild type salt sensitive rats, display increased mean arterial blood pressure following chronic exposure to a high salt diet. In contrast to wild type rats, p66Shc-Del rats display increased H2O2 renal production and are characterized by a reduction in renal function. The number of glomeruli is significantly reduced in adult p66Shc-Del rats. SIGNIFICANCE: Since low nephron number is an established risk factor for kidney disease and hypertension in humans and rodents, our data suggest that H2O2 renal production, caused by irregular signaling of p66Shc, could be critical in regulating nephrogenesis and that abnormal p66Shc signaling negatively impacts kidney development and renal function by increasing susceptibility to diabetic nephropathy and hypertension-induced nephropathy.


Assuntos
Peróxido de Hidrogênio/toxicidade , Hipertensão Renal/patologia , Glomérulos Renais/patologia , Nefrite/patologia , Néfrons/patologia , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Animais , Peróxido de Hidrogênio/metabolismo , Hipertensão Renal/induzido quimicamente , Hipertensão Renal/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Nefrite/induzido quimicamente , Nefrite/metabolismo , Néfrons/efeitos dos fármacos , Néfrons/metabolismo , Oxidantes/metabolismo , Oxidantes/toxicidade , Ratos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética
4.
FASEB J ; 35(7): e21751, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34156114

RESUMO

Rat Thy-1 nephritis (Thy-1N) is an animal model of human mesangioproliferative glomerulonephritis (MsPGN), accompanied by glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition. Although sublytic C5b-9 formed on GMC membrane could induce cell proliferation, the mechanism is still unclear. In this study, we first demonstrated that the level of SRY related HMG-BOX gene 9 (SOX9), general control nonderepressible 5 (GCN5), fibroblast growth factor 1 (FGF1) and platelet-derived growth factor α (PDGFα) was all elevated both in the renal tissues of Thy-1N rats (in vivo) and in the GMCs (in vitro) with sublytic C5b-9 stimulation. Then, we not only discovered that sublytic C5b-9 caused GMC proliferation through increasing SOX9, GCN5, FGF1 and PDGFα expression, but also proved that SOX9 and GCN5 formed a complex and combined with FGF1 and PDGFα promoters, leading to FGF1 and PDGFα gene transcription. More importantly, GCN5 could mediate SOX9 acetylation at lysine 62 (K62) to enhance SOX9 binding to FGF1 or PDGFα promoter and promote FGF1 or PDGFα synthesis and GMC proliferation. Besides, the experiments in vivo also showed that FGF1 and PDGFα expression, GMC proliferation and urinary protein secretion in Thy-1N rats were greatly reduced by silencing renal SOX9, GCN5, FGF1 or PDGFα gene. Furthermore, the renal tissues of MsPGN patients also exhibited positive expression of these genes mentioned above. Collectively, our findings indicate that GCN5, SOX9 and FGF1/PDGFα can form an axis and play an essential role in sublytic C5b-9-triggered GMC proliferation, which might provide a novel insight into the pathogenesis of Thy-1N and MsPGN.


Assuntos
Proliferação de Células/genética , Proliferação de Células/fisiologia , Complexo de Ataque à Membrana do Sistema Complemento/genética , Rim/fisiologia , Células Mesangiais/fisiologia , Nefrite/genética , Transcrição Genética/genética , Acetilação , Animais , Linhagem Celular , Matriz Extracelular/genética , Fator 1 de Crescimento de Fibroblastos/genética , Humanos , Masculino , Fator de Crescimento Derivado de Plaquetas/genética , Regiões Promotoras Genéticas/genética , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/genética , Antígenos Thy-1/genética , Fatores de Transcrição de p300-CBP/genética
5.
BMJ Case Rep ; 14(6)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34083191

RESUMO

The diagnosis of elderly-onset IgA vasculitis (IgAV) and its prognosis can be difficult to ascertain because of its rarity and the frequent presence of comorbidities. Furthermore, the treatment of elderly-onset IgAV remains controversial. We report a case of IgAV in an 87-year-old patient. Renal involvement was detected early during the IgAV follow-up. He was treated with low-dose corticosteroid and azathioprine, which led to a complete remission without any adverse effects. This suggests that precise intervention with early diagnosis and careful renal follow-up may prevent renal failure and that low-dose steroids with azathioprine can be an effective treatment for elderly-onset IgAV with nephritis.


Assuntos
Nefrite , Púrpura de Schoenlein-Henoch , Vasculite , Corticosteroides , Idoso , Idoso de 80 Anos ou mais , Azatioprina , Humanos , Imunoglobulina A , Masculino , Vasculite/tratamento farmacológico
6.
Phytomedicine ; 87: 153585, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34044255

RESUMO

BACKGROUND: Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. PURPOSE: To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. METHODS: The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro. RESULTS: The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/ß-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro, API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC50 values of 0.64 ± 0.14 µM and 2.63 ± 0.69 µM, respectively. CONCLUSIONS: API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/ß-catenin pathway, and thus it might be a potential therapy to HN.


Assuntos
Apigenina/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Hiperuricemia/tratamento farmacológico , Nefropatias/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Animais , Apigenina/administração & dosagem , Creatinina/sangue , Relação Dose-Resposta a Droga , Fibrose , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Células HEK293 , Humanos , Hiperuricemia/induzido quimicamente , Hiperuricemia/fisiopatologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Nefrite/tratamento farmacológico , Nefrite/patologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
7.
Free Radic Biol Med ; 171: 42-54, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933600

RESUMO

Extracellular vesicles can mediate cell-to-cell communication, or relieve the parent cell of harmful substances, in order to maintain cellular integrity. The content of extracellular vesicles includes miRNAs, mRNAs, growth factors, complement factors, cytokines, chemokines and receptors. These may contribute to inflammatory and infectious diseases by the exposure or transfer of potent effectors that induce vascular inflammation by leukocyte recruitment and thrombosis. Furthermore, vesicles release cytokines and induce their release from cells. Extracellular vesicles possess immune modulatory and anti-microbial properties, and induce receptor signaling in the recipient cell, not least by the transfer of pro-inflammatory receptors. Additionally, the vesicles may carry virulence factors systemically. Extracellular vesicles in blood and urine can contribute to the development of kidney diseases or exhibit protective effects. In this review we will describe the role of EVs in inflammation, thrombosis, immune modulation, angiogenesis, oxidative stress, renal tubular regeneration and infection. Furthermore, we will delineate their contribution to renal ischemia/reperfusion, vasculitis, glomerulonephritis, lupus nephritis, thrombotic microangiopathies, IgA nephropathy, acute kidney injury, urinary tract infections and renal transplantation. Due to their content of miRNAs and growth factors, or when loaded with nephroprotective modulators, extracellular vesicles have the potential to be used as therapeutics for renal regeneration.


Assuntos
Doenças Transmissíveis , Vesículas Extracelulares , Nefrite , Humanos , Rim , Túbulos Renais
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(4): 338-342, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33840404

RESUMO

OBJECTIVE: To study the efficacy and safety of mycophenolate mofetil (MMF) versus cyclophosphamide (CTX) in the treatment of children with Henoch-Schönlein purpura nephritis (HSPN) and nephrotic-range proteinuria. METHODS: A prospective clinical trial was conducted in 68 pediatric patients who were admitted to the Department of Nephrology, Children's Hospital Affiliated to Capital Institute of Pediatrics and who were diagnosed with HSPN and nephrotic-range proteinuria from August 2016 to November 2019. The patients were randomly divided into two groups:MMF treatment (n=33) and CTX treatment (n=35). The two groups were compared in terms of complete remission rate, response rate (complete remission + partial remission), urinary protein clearance time, and adverse events. RESULTS: At months 3, 6, and 12 of treatment, there was no significant difference in the complete remission rate and the response rate between the MMF treament and CTX treatment groups (P > 0.05). There was also no significant difference between the two groups in the urinary protein clearance time and the incidence rate of adverse events (P > 0.05). CONCLUSIONS: MMF and CTX have similar efficacy and safety in the treatment of HSPN children with nephrotic-range proteinuria.


Assuntos
Nefrite , Púrpura de Schoenlein-Henoch , Criança , Ciclofosfamida/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Ácido Micofenólico/efeitos adversos , Nefrite/tratamento farmacológico , Estudos Prospectivos , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Púrpura de Schoenlein-Henoch/complicações , Púrpura de Schoenlein-Henoch/tratamento farmacológico , Estudos Retrospectivos
9.
Life Sci ; 277: 119512, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862116

RESUMO

AIM: Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Nevertheless, there is a lack of information available in regarding its nephrotoxicity. The purpose of this work was to investigate the impact of cyanocobalamin (COB) and/or calcitriol (CAL) injections on TAMO-induced nephrotoxicity. MAIN METHODS: Animals were allocated into five groups as follows: normal control group; TAMO (45 mg/kg) administered group; TAMO+COB (6mg/kg, i.p) treated group; TAMO+CAL (0.3 µg/kg, i.p) treated group; TAMO+COB+CAL combination groups. KEY FINDINGS: Renal injury induced by TAMO was confirmed by the alteration in renal function parameters in the serum (urea and creatinine), as well as in the urine (creatinine clearance, total protein and albumin). These results were supported by histopathological examination. Upregulation of renal inflammatory parameters; tumor necrosis factor (TNF)-α, interleukin (IL)-6, C-reactive protein (CRP); and transforming growth factor (TGF)-ß1 as well as in protein expression of nuclear factor-kappa B (NF-κB) and cleaved caspase-3 were observed to a greater extent in the TAMO-treated rats compared with the control. Renal fibrosis was also evidenced by a elevation in renal L-hydroxyproline level as well as by histomorphological collagen deposition in TAMO-treated groups compared to the control group. Administration of COB and/or CAL concurrently with TAMO significantly ameliorated the deviation in the above-studied parameters and improved the histopathological renal picture. SIGNIFICANCE: Inhibition of NF-κß-mediated inflammation and caspase-3-induced apoptosis are possible renoprotective mechanisms of COB and/or CAL against TAMO nephrotoxicity, which was more noticeable in the TAMO group treated with the combination of the two vitamins in question.


Assuntos
Calcitriol/farmacologia , Tamoxifeno/efeitos adversos , Vitamina B 12/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Animais , Apoptose , Nitrogênio da Ureia Sanguínea , Calcitriol/metabolismo , Caspase 3/metabolismo , Creatinina/sangue , Feminino , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Testes de Função Renal , NF-kappa B/metabolismo , Nefrite/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Vitamina B 12/metabolismo
11.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921823

RESUMO

Hypertension induces renal fibrosis or tubular interstitial fibrosis, which eventually results in end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is one of the underlying mechanisms of renal fibrosis. Though previous studies showed that Ecklonia cava extracts (ECE) and dieckol (DK) had inhibitory action on angiotensin (Ang) I-converting enzyme, which converts Ang I to Ang II. It is known that Ang II is involved in renal fibrosis; however, it was not evaluated whether ECE or DK attenuated hypertensive nephropathy by decreasing EMT. In this study, the effect of ECE and DK on decreasing Ang II and its down signal pathway of angiotensin type 1 receptor (AT1R)/TGFß/SMAD, which is related with the EMT and restoring renal function in spontaneously hypertensive rats (SHRs), was investigated. Either ECE or DK significantly decreased the serum level of Ang II in the SHRs. Moreover, the renal expression of AT1R/TGFß/SMAD was decreased by the administration of either ECE or DK. The mesenchymal cell markers in the kidney of SHRs was significantly decreased by ECE or DK. The fibrotic tissue of the kidney of SHRs was also significantly decreased by ECE or DK. The ratio of urine albumin/creatinine of SHRs was significantly decreased by ECE or DK. Overall, the results of this study indicate that ECE and DK decreased the serum levels of Ang II and expression of AT1R/TGFß/SMAD, and then decreased the EMT and renal fibrosis in SHRs. Furthermore, the decrease in EMT and renal fibrosis could lead to the restoration of renal function. It seems that ECE or DK could be beneficial for decreasing hypertensive nephropathy by decreasing EMT and renal fibrosis.


Assuntos
Benzofuranos/uso terapêutico , Angiotensina II/metabolismo , Animais , Benzofuranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Dioxinas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Nefrite/tratamento farmacológico , Nefrite/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
12.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537809

RESUMO

Hypertensive nephropathy is the most common complication of hypertension, and is one of the main causes of end­stage renal disease (ESRD) in numerous countries. The basic pathological feature of hypertensive nephropathy is arteriolosclerosis followed by renal parenchymal damage. The etiology of this disease is complex, and its pathogenesis is mainly associated with renal hemodynamic changes and vascular remodeling. Despite the increased knowledge on the pathogenesis of hypertensive nephropathy, the current clinical treatment methods are still not effective in preventing the development of the disease to ESRD. Herbal medicine, which is used to relieve symptoms, can improve hypertensive nephropathy through multiple targets. Since there are few clinical studies on the treatment of hypertensive nephropathy with herbal medicine, this article aims to review the progress on the basic research on the treatment of hypertensive nephropathy with herbal medicine, including regulation of the renin angiotensin system, inhibition of sympathetic excitation, antioxidant stress and anti­inflammatory protection of endothelial cells, and improvement of obesity­associated factors. Herbal medicine with different components plays a synergistic and multi­target role in the treatment of hypertensive nephropathy. The description of the mechanism of herbal medicine in the treatment of hypertensive nephropathy will contribute towards the progress of modern medicine.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Medicina Herbária , Hipertensão Renal , Falência Renal Crônica , Nefrite , Estresse Oxidativo/efeitos dos fármacos , Humanos , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/metabolismo , Hipertensão Renal/fisiopatologia , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Nefrite/tratamento farmacológico , Nefrite/metabolismo , Nefrite/fisiopatologia
13.
Microb Pathog ; 152: 104770, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33545326

RESUMO

Chronic leptospirosis usually occurs during sublethal doses infection of susceptible animal and reservoir host, which typical symptom is interstitial nephritis, and leptospira urine, contaminating the environment and threatening other susceptible animals and humans. Dipotassium glycyrrhizinate (DG) is a replacement for glycyrrhizic acid, which exhibits anti-inflammation, immunomodulation effects. This study is to investigate whether DG relieves leptospira-induced nephritis. In vitro, DG inhibited the leptospira-induced transcription levels of IL-1ß, IL-6, TNF-α, RANTES, MCP-1 and iNOS, and protein levels of IL-1ß and TNF-α, and downregulated NF-κB and MAPK pathway in TCMK-1 cells. In vivo, DG attenuated the kidney histopathological change and downregulated the expression of IL-1ß and TNF-α, as well as reduced kidney leptospiral burden. In summary, DG alleviated leptospira-induced inflammation through inhibitory NF-κB and MAPK pathway, and DG decreased the renal colonization of leptospires in mice.


Assuntos
Leptospira interrogans , Leptospira , Leptospirose , Nefrite , Animais , Ácido Glicirrízico/farmacologia , Leptospirose/tratamento farmacológico , Camundongos
14.
Am J Physiol Renal Physiol ; 320(4): F608-F616, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33615891

RESUMO

Stimulator of interferon genes (STING) is an important adaptor in cytosolic DNA-sensing pathways. A recent study found that the deletion of STING ameliorated cisplatin-induced acute kidney injury (AKI), suggesting that STING could serve as a potential target for AKI therapy. Up to now, a series of small-molecule STING inhibitors/antagonists have been identified. However, none of the research was performed to explore the role of human STING inhibitors in AKI. Here, we investigated the effect of a newly generated covalent antagonist, H151, which targets both human and murine STING, in cisplatin-induced AKI. We found that H151 treatment significantly ameliorated cisplatin-induced kidney injury as shown by the improvement of renal function, kidney morphology, and renal inflammation. In addition, tubular cell apoptosis and increased renal tubular injury marker neutrophil gelatinase-associated lipocalin induced by cisplatin were also effectively attenuated in H151-treated mice. Moreover, the mitochondrial injury caused by cisplatin was also reversed as evidenced by improved mitochondrial morphology, restored mitochondrial DNA content, and reversed mitochondrial gene expression. Finally, we observed enhanced mitochondrial DNA levels in the plasma of patients receiving platinum-based chemotherapy compared with healthy controls, which could potentially activate STING signaling. Taken together, these findings suggested that H151 could be a potential therapeutic agent for treating AKI possibly through inhibiting STING-mediated inflammation and mitochondrial injury.NEW & NOTEWORTHY Although various stimulator of interferon genes (STING) inhibitors have been identified, no research was performed to investigate the role of human STING inhibitors in AKI. Here, we evaluated the effect of H151 targeting both human and murine STING on cisplatin-induced AKI and observed a protection against renal injury possibly through ameliorating inflammation and mitochondrial dysfunction.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cisplatino/farmacologia , Lipocalina-2/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Injúria Renal Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lipocalina-2/metabolismo , Camundongos , Mitocôndrias/metabolismo , Nefrite/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Toxicol Appl Pharmacol ; 416: 115465, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631230

RESUMO

Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN.


Assuntos
Anti-Inflamatórios/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Rim/efeitos dos fármacos , Nefrite/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Glicemia/metabolismo , Linhagem Celular , Quinase 9 Dependente de Ciclina/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Fibrose , Mediadores da Inflamação/metabolismo , Rim/enzimologia , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nefrite/enzimologia , Nefrite/etiologia , Nefrite/patologia , Fator de Transcrição AP-1/metabolismo
18.
J Endocrinol ; 248(3): 289-301, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33449915

RESUMO

The glucagon-like peptide-1 receptor (GLP1R) is expressed in the renal vasculature and known to be downregulated under hypertensive conditions in rats and humans. However, little is known about the regulation in other types of renal pathology involving vascular changes. This study investigates the expression of the GLP1R in renal vasculature after glomerular injury in the nephrotoxic nephritis mouse model, high cholesterol, and atherosclerosis in the Ldlr-/- mouse on Western diet, and ex vivo injury in an organ culture model. The immunohistochemical signal of the GLP1R was significantly decreased in arteries from mice with nephrotoxic nephritis after 42 days compared to 7 days and saline control (P < 0.05). Histological evaluation of kidneys from Ldlr-/- mice on Western diet showed a decreased GLP1R specific immunohistochemical signal (P < 0.05). The dilatory response to liraglutide was decreased in Western diet fed Ldlr-/- mice compared to C57Bl/6J controls (P < 0.05). Organ culture significantly decreased the immunohistochemical signal of the GLP1R (P <0.05) and the expression of Glp1r mRNA (P < 0.005) compared to fresh. Organ cultured vessels showed vascular smooth muscle cell remodelling as Acta2 expression was decreased (P < 0.005) and Ednrb was increased (P < 0.05). In conclusion, nephrotoxic nephritis and hypercholesterolaemia led to decreased GLP1R specific immunohistochemical signal. Ex vivo vascular injury in the organ culture model leads to a decrease in expression of GLP1R expressionand contractile VSMC specific markers and increase in expression of dedifferentiation markers suggestive of an inverse relationship between phenotypic switch of the VSMC and the expression of the GLP1R; however, the causal relationship remains elusive.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Artéria Renal/metabolismo , Doenças Vasculares/metabolismo , Animais , Feminino , Camundongos , Nefrite/metabolismo , Técnicas de Cultura de Órgãos
19.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(1): 49-54, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33476537

RESUMO

OBJECTIVE: To study the clinical effect and mechanism of total glucosides of paeony (TGP) in the adjuvant therapy for children with Henoch-Schönlein purpura nephritis (HSPN). METHODS: Sixty-four HSPN children with moderate proteinuria were divided into a TGP treatment group (n=34) and a routine treatment group (n=30) using a random number table. Thirty healthy children who underwent physical examination were enrolled as the healthy control group. The children in the routine treatment group were given conventional treatment alone, and those in the observation group were given TGP in addition to the conventional treatment. The two groups were compared in the clinical outcome after 4 weeks of treatment. The proportion of follicular helper T (Tfh) cells in peripheral blood and the plasma levels of interleukin-21 (IL-21) and interleukin-4 (IL-4) were measured in the healthy control group and the two HSPN groups. The changes in serum cystatin C (CysC) level and urinary alpha 1-microglobulin (A1M) concentration were compared before and after treatment in the two HSPN groups. RESULTS: Compared with the healthy children before treatment, the children with HSPN had higher proportion of Tfh cells and expression levels of IL-21 and IL-4 (P < 0.01). The TGP treatment group had a higher overall response rate to treatment than the routine treatment group (94% vs 67%, P < 0.05). After treatment, both groups had reductions in the proportion of Tfh cells in peripheral blood, the expression levels of IL-21, IL-4, serum CysC, and urinary A1M concentration. The TGP treatment group had greater reductions in these indices than the routine treatment group (P < 0.01). CONCLUSIONS: TGP has a marked clinical effect in the treatment of HSPN and can reduce the inflammatory response of the kidney and exert a protective effect on the kidney by inhibiting the proliferation of Tfh cells and downregulating the expression of IL-21 and IL-4 in plasma.


Assuntos
Nefrite , Paeonia , Púrpura de Schoenlein-Henoch , Criança , Glucosídeos/uso terapêutico , Humanos , Estudos Prospectivos , Púrpura de Schoenlein-Henoch/tratamento farmacológico
20.
Life Sci ; 274: 119109, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513393

RESUMO

The increasing incident of chronic kidney disease (CKD) in recent years might be related to a change in dietary habits, known as excessive salt intake. Given excessive salt promotes pathogenic T cells responses. Since the importance of macrophage in the development of CKD, we addressed the effect of high salt loading on in a rat CKD model. We observed that 5/6Nx rats receiving a high salt diet showed strongly enhanced macrophage infiltration and activation in the renal tissue accompanied by deteriorated renal inflammation. Then we used the microarray expression profiling to detect the effect of additional Nacl on peritoneal macrophage derived from 5/6Nx. The NaCl treatment of macrophage extracted from 5/6Nx rat elicited a strong pro-inflammatory phenotype characterized by enhanced proinflammatory cytokine production, increased expression of molecules mainly involved in immune response process. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased phosphorylation of STAT1. Taken together, our study demonstrated that high salt intake promotes immune activation of macrophages through the STAT1 independently and exacerbates the kidney accompanied by promotion of inflammation. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of CKD.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Nefrectomia/efeitos adversos , Nefrite/patologia , Cloreto de Sódio/toxicidade , Animais , Regulação da Expressão Gênica , Inflamação/induzido quimicamente , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Nefrite/induzido quimicamente , Nefrite/metabolismo , Nefrite/cirurgia , Ratos , Ratos Sprague-Dawley
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