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1.
J Asian Nat Prod Res ; 24(1): 76-87, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34937462

RESUMO

Renal fibrosis is a critical pathological process lead to a progressive loss of renal function. Jolkinolide B (JB) is a natural compound with anti-inflammatory activity from Euphorbia fischeriana Steud. The study evaluated the effect of JB on renal fibrosis in mice with unilateral ureteral obstruction (UUO). The results showed that JB could decrease renal fibrotic area, reduce phosphorylation of NF-κB p65 and the release of TNF-α, IL-6 and IL-1ß, restore the expression of vementin, α-SMA and E-cadherin, as well as TGF-ß1 and p-smad2/3. In conclusion, JB might reduce renal fibrosis by inhibiting inflammation induced by NF-κB pathway and EMT mediated by TGF-ß1/Smad pathway.


Assuntos
Obstrução Ureteral , Animais , Anti-Inflamatórios/farmacologia , Diterpenos , Transição Epitelial-Mesenquimal , Fibrose , Rim/patologia , Camundongos , Estrutura Molecular , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia
2.
Life Sci ; 289: 120230, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34919900

RESUMO

The application of atmospheric pressure low-temperature plasma (LTP) in medical treatment has received extensive attention owing to its redox regulatory and anti-inflammatory properties. Nephrotoxicity due to oxidative stress and inflammation is the main adverse effect of cisplatin. In the present study, rats with cisplatin-induced nephrotoxicity were treated with LTP to investigate its potential protective effect. The results showed that LTP treatment has multiple protective effects on cisplatin-induced nephrotoxicity. It significantly improved clinical indicators such as survival rate, water intake, food intake, body weight, and mobility, as well as physiological indexes such as reduced renal index and levels of serum urea, creatinine, and total bilirubin; pathological indicators such as reduced tubular injury, inflammatory infiltration, tubulointerstitial fibrosis, and apoptosis; cell survival indicators such as decreased protein levels of Caspase-3 and Bax and increased Bcl-2; anti-oxidation status such as reduced malondialdehyde content and increased activities of catalase, superoxide dismutase, and glutathione peroxidase; and reduced inflammatory factors such as TNF-α in kidney tissues. Specially, LTP treatment did not influence the anticancer effect of cisplatin as observed in the solid tumor mouse model established by subcutaneously inoculating H22 cells. Moreover, LTP did not influence the physiological and pathological indicators of normal rats, suggesting its biological safety. In conclusion, LTP can protect against cisplatin-induced nephrotoxicity through its anti-oxidation, anti-inflammation, and anti-apoptosis effects, without influencing the anticancer effect of cisplatin.


Assuntos
Cisplatino , Regulação da Expressão Gênica/efeitos dos fármacos , Nefropatias , Rim , Gases em Plasma/farmacologia , Animais , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Ratos Wistar
3.
Curr Opin Nephrol Hypertens ; 31(1): 36-46, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34846312

RESUMO

PURPOSE OF REVIEW: Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. RECENT FINDINGS: SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. SUMMARY: In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.


Assuntos
Injúria Renal Aguda , COVID-19 , Insuficiência Renal Crônica , Trombose , Injúria Renal Aguda/etiologia , COVID-19/complicações , Fibrose , Humanos , Inflamação , Rim/patologia , Lipídeos , Insuficiência Renal Crônica/patologia , SARS-CoV-2 , Trombose/patologia
4.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166296, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34718120

RESUMO

Bisphenol-A (BPA), a chemical -xenoestrogen- used in the production of the plastic lining of food and beverage containers, is present in the urine of almost the entire population. Recent studies have shown that BPA exposure is associated with podocytopathy, increased urinary albumin excretion (UAE), and hypertension. Since these changes are characteristic of early diabetic nephropathy (DN), we explored the renal effects of BPA and diabetes including the potential role of sexual dimorphism. Male and female mice were included in the following animals' groups: control mice (C), mice treated with 21.2 mg/kg of BPA in the drinking water (BPA), diabetic mice induced by streptozotocin (D), and D mice treated with BPA (D + BPA). Male mice form the D + BPA group died by the tenth week of the study due probably to hydro-electrolytic disturbances. Although BPA treated mice did not show an increase in serum creatinine, as observed in D and D + BPA groups, they displayed similar alteration to those of the D group, including increased in kidney damage biomarkers NGAL and KIM-1, UAE, hypertension, podocytopenia, apoptosis, collapsed glomeruli, as well as TGF-ß, CHOP and PCNA upregulation. UAE, collapsed glomeruli, PCNA staining, TGF-ß, NGAL and animal survival, significantly impaired in D + BPA animals. Moreover, UAE, collapsed glomeruli and animal survival also displayed a sexual dimorphism pattern. In conclusion, oral administration of BPA is capable of promoting in the kidney alterations that resemble early DN. Further translational studies are needed to clarify the potential role of BPA in renal diseases, particularly in diabetic patients.


Assuntos
Compostos Benzidrílicos/toxicidade , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Rim/efeitos dos fármacos , Fenóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/patologia , Feminino , Receptor Celular 1 do Vírus da Hepatite A/genética , Humanos , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Rim/patologia , Lipocalina-2/genética , Masculino , Camundongos , Caracteres Sexuais
5.
Exp Cell Res ; 410(2): 112965, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34896075

RESUMO

IFN-γ-inducible protein 10 (IP-10, CXCL10) has been widely demonstrated to be involved in multiple kidney pathological processes. However, the role of CXCL10 in renal fibrosis remains unclear. In this study, Cxcl10-deficient (Cxcl10-/-) mice were used to generate the unilateral ureteral obstruction (UUO) model. The level of renal fibrosis and inflammatory cell infiltration was examined in vivo and the effects of CXCL10 on EMT process of HK-2 cells was investigated in vitro. We observed that the injury degree of renal tissue and the collagen deposition levels were lighter and the expression of α-SMA, collagen I and fibronectin was significantly reduced in Cxcl10-/- mice, while the expression of E-cadherin was increased. However, interstitial F4/80-positive macrophages and CD4-positive T lymphocytes were unaffected by knockout of Cxcl10. Furthermore, IFN-γ or CXCL10 stimulation could obviously promote the expression of α-SMA, collagen I, fibronectin and reduce the expression of E-cadherin in HK-2 cells, which could be inhibited by transfection of Cxcl10-siRNA. Our findings suggested Cxcl10 knockout could reduce renal dysfunction and inhibit renal fibrosis through regulating EMT process of renal tubular epithelial cells in murine UUO model. These results may provide a novel insight into the mechanism and a potential therapy target of renal fibrosis.


Assuntos
Quimiocina CXCL10/deficiência , Transição Epitelial-Mesenquimal , Nefropatias/metabolismo , Nefropatias/patologia , Animais , Proliferação de Células , Quimiocina CXCL10/metabolismo , Fibrose , Humanos , Rim/patologia , Rim/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obstrução Ureteral/patologia
6.
Chem Biol Interact ; 352: 109781, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34922902

RESUMO

Diabetic nephropathy (DN) is one of the manifestations of systemic microangiopathy in diabetes. Trifolium alexandrinum extract (TAE) contains biologically active phenolic compounds such as hesperetin (HES) and quercetin, possess various pharmacological properties, including anti-inflammatory, and anti-oxidative potentials. The present study aimed to assess the therapeutic effects and mechanisms underlying the anti-diabetic, antioxidant, and anti-inflammatory effects of HES and quercetin extracted from TAE, and TAE in STZ-induced DN. Male albino rats (170 ± 10 g) were divided into group (1); control rats and groups (2-5); diabetic/HFD were intraperitoneal (i.p.) injected with STZ (35 mg/kg), diabetic rats were randomly classified into STZ, STZ + HES (40 mg/kg), STZ + quercetin (50 mg/kg), and STZ + TAE (200 mg/kg) groups. After 5 weeks, blood and kidney samples were collected for further biochemical, western blotting and histopathological studies. Serum renal functions, renal oxidative status biomarkers and proinflammatory cytokines were determined. The results revealed that there were significant increases in urea, BUN, creatinine, ALP, total protein, albumin, and globulin with a significant decrease in Na+ and K+ levels, as well as significant elevation in TBARS, TGF-ß, TNF-α, IL-6 and the expression levels of GSK-3ß, as well as significant decline in TAC, GSH and CAT levels in STZ-treated group compared to the control rats. The previous deleterious alterations were significantly ameliorated after the treatment of diabetic rats with HES, quercetin and TAE. In conclusion, our data demonstrated that HES, quercetin and TAE could be used as potent therapeutic agents to counter DN through antioxidant, anti-inflammatory, and antidiabetic effects.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Hesperidina/farmacologia , Fitoterapia , Quercetina/farmacologia , Trifolium/química , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
7.
Cells ; 10(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944007

RESUMO

In the context of transplantation, complement activation is associated with poor prognosis and outcome. While complement activation in antibody-mediated rejection is well-known, less is known about complement activation in acute T cell-mediated rejection (TCMR). There is increasing evidence that complement contributes to the clearance of apoptotic debris and tissue repair. In this regard, we have analysed published human kidney biopsy transcriptome data clearly showing upregulated expression of complement factors in TCMR. To clarify whether and how the complement system is activated early during acute TCMR, experimental syngeneic and allogeneic renal transplantations were performed. Using an allogeneic rat renal transplant model, we also observed upregulation of complement factors in TCMR in contrast to healthy kidneys and isograft controls. While staining for C4d was positive, staining with a C3d antibody showed no C3d deposition. FACS analysis of blood showed the absence of alloantibodies that could have explained the C4d deposition. Gene expression pathway analysis showed upregulation of pro-apoptotic factors in TCMR, and apoptotic endothelial cells were detected by ultrastructural analysis. Monocytes/macrophages were found to bind to and phagocytise these apoptotic cells. Therefore, we conclude that early C4d deposition in TCMR may be relevant to the clearance of apoptotic cells.


Assuntos
Apoptose , Complemento C4b/metabolismo , Transplante de Rim , Fragmentos de Peptídeos/metabolismo , Animais , Biópsia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Rim/patologia , Rim/ultraestrutura , Masculino , Ratos Endogâmicos BN , Receptores de Morte Celular/metabolismo , Transdução de Sinais , Transcriptoma/genética , Transplante Homólogo
8.
Cell Mol Life Sci ; 79(1): 53, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34950960

RESUMO

SIRT6 is an NAD+ dependent deacetylase that belongs to the mammalian sirtuin family. SIRT6 is mainly located in the nucleus and regulates chromatin remodeling, genome stability, and gene transcription. SIRT6 extensively participates in various physiological activities such as DNA repair, energy metabolism, oxidative stress, inflammation, and fibrosis. In recent years, the role of epigenetics such as acetylation modification in renal disease has gradually received widespread attention. SIRT6 reduces oxidative stress, inflammation, and renal fibrosis, which is of great importance in maintaining cellular homeostasis and delaying the chronic progression of kidney disease. Here, we review the structure and biological function of SIRT6 and summarize the regulatory mechanisms of SIRT6 in kidney disease. Moreover, the role of SIRT6 as a potential therapeutic target for the progression of kidney disease will be discussed. SIRT6 plays an important role in kidney disease. SIRT6 regulates mitochondrial dynamics and mitochondrial biogenesis, induces G2/M cycle arrest, and plays an antioxidant role in nephrotoxicity, IR, obstructive nephropathy, and sepsis-induced AKI. SIRT6 prevents and delays progressive CKD induced by hyperglycemia, kidney senescence, hypertension, and lipid accumulation by regulating mitochondrial biogenesis, and has antioxidant, anti-inflammatory, and antifibrosis effects. Additionally, hypoxia, inflammation, and fibrosis are the main mechanisms of the AKI-to-CKD transition. SIRT6 plays a critical role in the AKI-to-CKD transition and kidney repair through anti-inflammatory, antifibrotic, and mitochondrial quality control mechanisms. AKI Acute kidney injury, CKD Chronic kidney disease.


Assuntos
Nefropatias/metabolismo , Rim/metabolismo , Sirtuínas , Animais , Epigênese Genética , Humanos , Rim/citologia , Rim/patologia , Camundongos , Mitocôndrias/metabolismo , Sirtuínas/química , Sirtuínas/fisiologia
9.
Cells ; 10(12)2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34943853

RESUMO

CCL17, a chemotactic cytokine produced by macrophages, is known to promote inflammatory and fibrotic effects in multiple organs, but its role in mediating renal fibrosis is unclear. In our study cohort of 234 chronic kidney disease (CKD) patients and 65 healthy controls, human cytokine array analysis revealed elevated CCL17 expression in CKD that correlated negatively with renal function. The area under the receiver operating characteristic curve of CCL17 to predict the development of CKD stages 3b-5 was 0.644 (p < 0.001), with the optimal cut-off value of 415.3 ng/mL. In vitro over-expression of CCL17 in HK2 cells had no effect on cell viability, but increased cell motility and the expression of α-SMA, vimentin and collagen I, as shown by western blot analysis. In a unilateral ureteral obstruction (UUO) mouse model, we observed significantly increased interstitial fibrosis and renal tubule dilatation by Masson's Trichrome and H&E staining, and markedly increased expression of CCL17, vimentin, collagen I, and α-SMA by IHC stain, qRTPCR, and western blotting. CCL17 induced renal fibrosis by promoting the epithelial-mesenchymal transition, resulting in ECM accumulation. CCL17 may be a useful biomarker for predicting the development of advanced CKD.


Assuntos
Quimiocina CCL17/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Ciclo Celular , Movimento Celular/genética , Sobrevivência Celular/genética , Quimiocina CCL17/genética , Transição Epitelial-Mesenquimal/genética , Fibrose , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Regulação para Cima/genética , Obstrução Ureteral/genética , Obstrução Ureteral/patologia
10.
Sci Rep ; 11(1): 24479, 2021 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-34966177

RESUMO

Systematic registration and examination of biopsy-related data in Central and Eastern Europe are scarce, while the health condition of the population is worse compared to other more developed countries. We aim to create a database and analyze the distribution and temporal variation of the renal biopsy diagnoses in Hungary, including the effect of the recent coronavirus pandemic. The diagnoses were standardized according to the recommendation of the European Renal Association. Native biopsy samples processed between January 1, 2006, and December 31, 2020, were analyzed. During the 15 years, 2140 native kidney biopsies were performed. The number of samples increased from 24.5 to 57.9 per million person-years and the median age from 37 to 51 years (p < 0.0001). The predominance of glomerular diseases was stable. The most frequent glomerulopathy was IgA nephropathy (21.5%), followed by focal segmental glomerulosclerosis (17.7%), and membranous nephropathy (15.7%). Trends showed the rise of ANCA-associated vasculitis. During the coronavirus pandemic, there was a decrease in the number of kidney biopsies and the proportion of membranous nephropathies. The diagnostic trends in our database showed increasing biopsy rates among the elderly and the growing frequencies of age-related diseases, which emphasizes the importance of altering medical focus according to demographic changes in this area.


Assuntos
Nefropatias/epidemiologia , Nefropatias/patologia , Rim/patologia , Adulto , Distribuição por Idade , Biópsia/métodos , Feminino , Glomerulonefrite/patologia , Glomerulonefrite Membranosa/patologia , Humanos , Hungria/epidemiologia , Incidência , Nefropatias/complicações , Masculino , Pessoa de Meia-Idade , Nefrectomia , Estudos Retrospectivos
11.
Urologiia ; (6): 47-50, 2021 Dec.
Artigo em Russo | MEDLINE | ID: mdl-34967164

RESUMO

INTRODUCTION: The high prevalence of kidney diseases caused by urinary tract obstruction has led to the need for experimental studies of the dynamics of pathological processes in their lesions. Despite the fact that the general patterns of development of obstructive uropathy are known, the features of renal tissue damage, in particular structural and molecular biological changes in this pathology, remain insufficiently studied. OBJECTIVE: to study the dynamics of changes in the phenotype of epithelial cells of the nephron of an obstructive kidney with unilateral ureteral obstruction using an experimental model. MATERIALS AND METHODS: The experimental study was carried out on the basis of the Rostov State Medical University. The model of unilateral ureteral obstruction was reproduced in adult rabbits. The studies were carried out on the 7th, 14th and 21st days of complete obstruction of the left ureter. Immunophenotyping of obstructive kidney tissue samples was performed for markers of epithelial phenotype (cytokeratin 7, E-cadherin) and mesenchymal phenotype (vimentin, - smooth muscle actin). RESULTS: The sequence of changes in the phenotype of nephron epithelial cells during ureteral obstruction has been established. The first signs of an epithelial-mesenchymal transition (EMT) appear by day 7 in the form of a decrease in visualization of markers of the epithelial phenotype. On the 14th day, the expression of both epithelial and mesenchymal markers is noted. Significant changes in the phenotype of nephron epithelial cells: loss of epithelial markers (cytokeratin 7, E-cadherin) and the acquisition of mesenchymal markers (vimentin, - smooth muscle actin), are noted by the 21st day of the experiment. CONCLUSION: An experimental model of unilateral ureteral obstruction revealed the transformation of the nephron tubule cell phenotype from epithelial to mesenchymal.


Assuntos
Nefropatias , Obstrução Ureteral , Animais , Transição Epitelial-Mesenquimal , Fibrose , Rim/patologia , Nefropatias/patologia , Néfrons , Coelhos , Obstrução Ureteral/complicações
13.
Nat Commun ; 12(1): 5760, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608135

RESUMO

Metastasis is the principal cause of cancer related deaths. Tumor invasion is essential for metastatic spread. However, determinants of invasion are poorly understood. We addressed this knowledge gap by leveraging a unique attribute of kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes into the heart. Over a decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection for grossly invasive tumors at UT Southwestern Kidney Cancer Program. In this study, we perform comprehensive histological analyses, integrate multi-region genomic studies, generate in vivo models, and execute functional studies to define tumor invasion and metastatic competence. We find that invasion is not always associated with the most aggressive clone. Driven by immediate early genes, invasion appears to be an opportunistic trait attained by subclones with diverse oncogenomic status in geospatial proximity to vasculature. We show that not all invasive tumors metastasize and identify determinants of metastatic competency. TT associated with metastases are characterized by higher grade, mTOR activation and a particular immune contexture. Moreover, TT grade is a better predictor of metastasis than overall tumor grade, which may have implications for clinical practice.


Assuntos
Carcinoma de Células Renais/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Trombose/genética , Idoso , Animais , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Feminino , Humanos , Rim/irrigação sanguínea , Rim/patologia , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estudos Prospectivos , RNA-Seq , Fatores de Risco , Trombose/patologia , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
14.
FASEB J ; 35(11): e21987, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34662459

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is associated with the formation of renal cysts. We have devised a therapeutic approach, based on reversing the cyst phenotype from secretion to absorption by using VX-809, a modulator of the cystic fibrosis transmembrane regulator trafficking and processing. Our goal is to test VX-809 in RC/RC mice bearing the R3277C human mutation to demonstrate its therapeutic potential. We found that by 5 months of age, RC/RC mice had large cysts and impaired renal function, but when treated with VX-809 between the ages of 3 and 5 months, or 6 and 8 months, the cyst area was reduced in both groups, suggesting that VX-809 had shrunk previously existing cysts. After 2 months of treatment, the cyst size was lower than that of untreated animals of the same age. Our co-localization studies confirmed that cystic fibrosis transmembrane conductance regulator (CFTR) is found predominately at the apical membrane in the untreated animals of each age group, consistent with its role in Cl- secretion; after VX-809 treatment, the basolateral membrane co-localization of CFTR increased ~4-fold, accompanied by a decrease of ~2-3-fold in its apical co-localization, indicating that VX-809 alters the phenotype to favor fluid absorption. Sodium/hydrogen exchanger and epithelial sodium channel, found in normal kidneys at the apical membrane, were almost absent from the cysts. VX-809 restored both levels toward normal. HSP27 is highly expressed in RC/RC mice and lowered toward normal by VX-809. Our demonstration of cyst reduction, improved renal function, and generation of an absorptive phenotype all strongly support the therapeutic potential of VX-809 as a treatment for ADPKD. We show here in an animal model of slowly progressing cyst formation typical of human ADPKD that VX-809 reduces the growth of already established cysts. The magnitude of the effect in the RC/RC mouse model when compared to previous experiments using the same mouse model to evaluate tolvaptan indicates that CFTR modulators warrant further development as a treatment for ADPKD.


Assuntos
Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/farmacologia , Cistos/tratamento farmacológico , Rim , Rim Policístico Autossômico Dominante/tratamento farmacológico , Animais , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638853

RESUMO

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner. In vitro, NU7441 (a DNA-PK kinase inhibitor) reduced MDCK cyst growth by up to 52% after long-term treatment over 6-12 days. Although human ADPKD cell lines (WT9-7/WT9-12) did not exhibit synthetic lethality in response to DNA-PK kinase inhibition compared to normal human kidney cells (HK-2), the combination of low-dose NU7441 enhanced the anti-proliferative effects of sirolimus in WT9-7 and WT9-12 cells by 17 ± 10% and 11 ± 7%, respectively. In conclusion, these preliminary data suggest that DNA-PK mediates kidney cyst growth in vivo without a synthetically lethal interaction, conferring cell-specificity in human ADPKD cells. NU7441 enhanced the anti-proliferative effects of rapamycin complex 1 inhibitors, but the effect was modest.


Assuntos
Cistos/genética , Proteína Quinase Ativada por DNA/genética , Perfilação da Expressão Gênica/métodos , Rim/metabolismo , Rim Policístico Autossômico Dominante/genética , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cromonas/farmacologia , Cistos/tratamento farmacológico , Cistos/enzimologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Cães , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Rim/patologia , Células Madin Darby de Rim Canino , Morfolinas/farmacologia , Rim Policístico Autossômico Dominante/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/genética
16.
Int J Mol Sci ; 22(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34639002

RESUMO

Renal toxicity is a serious side effect that hinders the use of cisplatin, a commonly used and effective chemotherapeutic agent. Meanwhile, quinacrine is an FDA approved drug that has been stated for its anti-inflammatory effect. Thus, we investigated the ameliorative effect of quinacrine against cisplatin-induced renal toxicity. Single intraperitoneal (i.p.) 10 mg/kg cisplatin administration induced renal injury in rats. Our results showed that 10 mg/kg/day quinacrine decreased the mortality rate of rats from 46.15% (cisplatin group) to 12.5%, and significantly decreased renal tissue fibrosis, relative kidney to body weight ratio, serum creatinine and urea levels compared with the cisplatin group. Indeed, quinacrine significantly decreased renal malondialdehyde concentration and increased renal total antioxidant capacity, compared with the cisplatin group. Furthermore, quinacrine caused significant upregulation of renal sirtuin-1 (SIRT-1) with significant downregulation of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α). Moreover, quinacrine significantly blocked cisplatin-induced apoptosis, which was made evident by downregulating renal apoptotic proteins (BAX and p53) and upregulating the renal anti-apoptotic protein BCL2, compared with the cisplatin group. In conclusion, this study demonstrates, for the first time, that quinacrine alleviates cisplatin-induced renal toxicity via upregulating SIRT-1, downregulating inflammatory markers (ICAM-1 and TNF-α), reducing oxidative stress, and inhibiting apoptosis.


Assuntos
Cisplatino/efeitos adversos , Nefropatias/etiologia , Nefropatias/metabolismo , Quinacrina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/diagnóstico , Nefropatias/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos
17.
Medicine (Baltimore) ; 100(37): e27077, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34664831

RESUMO

RATIONALE: Lupus podocytopathy (LP) is an entity that is increasingly being reported in the literature on systemic lupus erythematosus (SLE). LP is characterized by nephrotic syndrome in SLE patients with diffuse glomerular podocyte foot process effacement and no immune complex deposits along the capillary loops. Histologically, LP typically mimics minimal change disease or primary focal segmental glomerulosclerosis (FSGS) on a background of ISN/RPS class I or II lupus nephritis. In situations where there are coexistent glomerular diseases, however, LP may be easily masked by background lesions and overlapping clinical symptoms. PATIENT CONCERNS: We report the case of a 24-year-old woman with type I diabetes, hypertension, psoriasis/rash, and intermittent arthritis who presented with abrupt onset of severe nephrotic proteinuria and renal insufficiency. Renal biopsy revealed nodular glomerulosclerosis and FSGS. Immune deposits were not identified by immunofluorescence or electron microscopy. Ultrastructurally, there was diffuse glomerular basement membrane thickening and over 90% podocyte foot process effacement. With no prior established diagnosis of SLE, the patient was initially diagnosed with diabetic nephropathy with coexistent FSGS, and the patient was started on angiotensin-converting enzyme inhibitors (ACEI) and diuretics. However, nephrotic proteinuria persisted and renal function deteriorated. The patient concurrently developed hemolytic anemia with pancytopenia. DIAGNOSES: Subsequent to the biopsy, serologic results showed positive autoantibodies against double strand DNA (dsDNA), Smith antigen, ribonucleoprotein (RNP), and Histone. A renal biopsy was repeated, revealing essentially similar findings to those of the previous biopsy. Integrating serology and clinical presentation, SLE was favored. The pathology findings were re-evaluated and considered to be most consistent with LP and coexistent diabetic nephropathy, with superimposed FSGS either as a component of LP or as a lesion secondary to diabetes or hypertension. INTERVENTIONS: The patient was started on high-dose prednisone at 60 mg/day, with subsequent addition of mycophenolate mofetil and ACEI, while prednisone was gradually tapered. OUTCOMES: The patient's proteinuria, serum creatinine, complete blood counts, skin rash, and arthritis were all significantly improved. CONCLUSION: The diagnosis of LP when confounded by other glomerular diseases that may cause nephrotic syndrome can be challenging. Sufficient awareness of this condition is necessary for the appropriate diagnosis and treatment.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Sistemas de Infusão de Insulina , Rim/patologia , Rim/fisiopatologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/fisiopatologia , Prednisona/uso terapêutico , Adulto Jovem
18.
Arch Biochem Biophys ; 713: 109063, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34695409

RESUMO

Although FGF21 ameliorates diabetic nephropathy (DN), the efficacy is not satisfactory. Studies demonstrate that FGF21 combined with Insulin exhibits reciprocal sensitization on glucose and lipid metabolism in mice with type 2 diabetes. However, therapeutic effect of combined use of FGF21 and Insulin on DN has not been reported. Therefore, this study explored therapeutic effect and mechanism of combined use of FGF21 and Insulin on DN. Our results showed that compared with Insulin or FGF21 alone, FGF21 combined with Insulin further ameliorated blood glucose, HbAlc, OGTT, renal function, liver function, blood lipid, histopathological changes, oxidative stress and AGEs in the mice of DN (BKS-Leprem2Cd479/Gpt). Moreover, FGF21 combined with Insulin further reduced expressions of IL-1ß, IL-6, TNF-α via promoting M1 type macrophage into M2 type macrophage. Results of real-time PCR and Western blot showed that FGF21 combined with Insulin upregulated the expressions of autophagy related genes LC3-Ⅱ and BCL-1. Mesangial cells play an important role in the pathological changes of DN mice. However, the effect of FGF21 on mesangial cells has not been reported. In this study, d-glucose was used in high glucose (HG) model in mesangial cells. The results showed that FGF21 significantly reduced the levels of OS, AGEs and cell overproliferation. Meanwhile, FGF21 significantly ameliorated autophagy level via upregulating the phosphorylation of AMPK and downregulating phosphorylation of mTOR. These effects were reversed in siRNA-ß-klotho transfected mesangial cells. In conclusion, our results demonstrate that combination FGF21 with Insulin exhibits a better therapeutic effect on DN compared with FGF21 or Insulin alone. This study provides a theoretical basis for combined used of FGF21 and Insulin as a new treatment for DN and further provides theoretical support for application of FGF21 in treatment of DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Glicemia/metabolismo , Nefropatias Diabéticas/patologia , Combinação de Medicamentos , Produtos Finais de Glicação Avançada/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
19.
Nutrients ; 13(10)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34684325

RESUMO

Hyperuricemia is the primary cause of gouty arthritis and other metabolic disorders. Eggshell membrane (EM) is an effective and safe supplement for curing pain and stiffness connected with osteoarthritis. However, the effect of EM on hyperuricemia is unclear. This study determines the effects of EM on potassium oxonate-injected hyperuricemia. Uric acid, creatinine, blood urea nitrogen concentrations in the serum, and xanthine oxidase activity in the liver are measured. Protein levels of renal urate transporter 1 (URAT1), organic anion transporters 1 (OAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette transporter G2 (ABCG2) in the kidney are determined with renal histopathology. The results demonstrate that EM reduces serum uric acid levels and increases urine uric acid levels in hyperuricemic rats. Moreover, EM downregulates renal URAT1 protein expression, upregulates OAT1 and ABCG2, but does not change GLUT9 expression. Additionally, EM does not change xanthine oxidase activity in the liver or the serum. EM also decreases uric acid uptake into oocytes expressing hURAT1. Finally, EM markedly reduces renal inflammation and serum interleukin-1ß levels. These findings suggest that EM exhibits antihyperuricemic effects by promoting renal urate excretion and regulating renal urate transporters. Therefore, EM may be useful in the prevention and treatment of gout and hyperuricemia.


Assuntos
Casca de Ovo/fisiologia , Hiperuricemia/urina , Injeções , Ácido Oxônico/administração & dosagem , Ácido Úrico/urina , Animais , Humanos , Hiperuricemia/sangue , Hiperuricemia/fisiopatologia , Inflamação/patologia , Inflamação/fisiopatologia , Rim/patologia , Rim/fisiopatologia , Testes de Função Renal , Masculino , Oócitos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Ratos Sprague-Dawley , Ácido Úrico/sangue , Xantina Oxidase/metabolismo , Xenopus
20.
Nutrients ; 13(10)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34684342

RESUMO

Plant-based low protein diets (LPDs) have gained popularity for managing chronic kidney disease (CKD) patients. The nutritional adequacy of these and other LPDs prescribed for CKD patients have not been carefully examined. This study assessed the nutrient composition of such LPDs and moderately high protein diets (MHPDs) that might be prescribed for patients in the Asia Pacific region with CKD who are not dialyzed or undergoing maintenance dialysis. Conventional diets containing at least 50% animal-based proteins and plant-based diets were also planned with protein prescriptions of 0.5 to 0.8 g/kg/day and MHPDs with protein prescriptions of 1.0 to 1.2 g/kg/day. Plant-based, lacto-, ovo-, and lacto-ovo-vegetarian and vegan LPDs and MHPDs were planned by replacing some or all of the animal proteins from the conventional diet. With 0.5 g protein/kg/day, all diets were below the Recommended Dietary Allowances (RDA) for at least one essential amino acid (EAA). At a protein prescription of 0.6 g/kg/day, only the conventional LPD met the RDA for all EAAs. This deficiency with the plant-based LPDs persisted even with several plant food substitutions. With a protein prescription ≥0.7 g/kg/day, all the plant-based and vegetarian LPDs provided the RDA for all EAA. The plant-based and vegetarian diets also contained relatively greater potassium, phosphorus, and calcium content but lower long-chain n-3 polyunsaturated fatty acids and vitamin B-12 than the conventional diet. Other essential micronutrients were commonly below the RDA even at higher protein intakes. The low contents of some essential micronutrients were found in both animal-based and plant-based diets. Prescription of all LPDs for CKD patients, especially plant-based and vegetarian LPDs, requires careful planning to ensure the adequacy of all nutrients, particularly essential amino acids. Consideration should be given to supplementing all animal-based and plant-based LPDs and MHPDs with multivitamins and certain trace elements.


Assuntos
Dieta , Modelos Teóricos , Estado Nutricional , Plantas , Insuficiência Renal Crônica/dietoterapia , Ácidos/análise , Animais , Dieta Rica em Proteínas , Dieta Vegetariana , Rim/patologia , Nutrientes/análise , Recomendações Nutricionais
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