Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.365
Filtrar
1.
Life Sci ; 241: 117187, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31863776

RESUMO

AIMS: Renal interstitial fibrosis (RIF) is marked by the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix deposition. The long noncoding RNA myocardial infarction-associated transcript (MIAT) facilitates RIF; however, the molecular mechanism of MIAT in RIF remains unclear. Here, we explored the possible underlying mechanisms through which MIAT modulates RIF. MATERIALS AND METHODS: MIAT expression in human renal fibrotic tissues and unilateral ureteral obstruction (UUO) model mice was detected by qPCR. Transforming growth factor ß1 (TGF-ß1) was introduced to stimulate the EMT in human renal proximal tubular epithelial (HK-2) cells. CCK8, EdU, transwell and wound healing assays were employed to measure cell viability, proliferation, and migration respectively. RNA immunoprecipitation (RIP) assays and dual luciferase reporter assays were applied to determine the relationships among MIAT, miR-145, and EIF5A2. KEY FINDINGS: MIAT was upregulated in human renal fibrotic tissues and UUO model mice compared with normal tissue adjacent to renal tumors and sham operation mice, respectively. MIAT knockdown reduced cell viability, proliferation, migration, and the EMT in HK-2 cells. Additionally, MIAT served as an endogenous sponge for miR-145 in the TGF-ß1-induced-EMT in HK-2 cells, as demonstrated by dual luciferase reporter assays and RIP assays. EIF5A2 was confirmed as a target of miR-145, and MIAT knockdown suppressed EIF5A2 expression by sponging miR-145. Downregulation of EIF5A2 partly reversed induction of the EMT by miR-145 inhibitor transfection. SIGNIFICANCE: MIAT promoted cell viability, proliferation, migration, and the EMT via regulation of the miR-145/EIF5A2 axis. These data established a potential therapy for RIF.


Assuntos
Transição Epitelial-Mesenquimal , Fibrose/patologia , Nefropatias/patologia , MicroRNAs/genética , Fatores de Iniciação de Peptídeos/metabolismo , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Obstrução Ureteral/patologia , Animais , Estudos de Casos e Controles , Fibrose/genética , Fibrose/metabolismo , Regulação da Expressão Gênica , Humanos , Nefropatias/genética , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo
2.
Int Braz J Urol ; 45(6): 1266-1269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31808416

RESUMO

We describe the rare case of a 61-year-old female with right ureteropelvic junction (UPJ) obstruction caused by metastatic cholangiocarcinoma. Her past medical history was notable for cholangiocarcinoma treated with neoadjuvant chemoradiation and two orthotopic liver transplants six years earlier. Urology was consulted when she presented with flank pain and urinary tract infection. Diagnostic workup demonstrated right UPJ obstruction. She was managed acutely with percutaneous nephrostomy. She subsequently underwent robotic pyeloplasty and intrinsic obstruction of the UPJ was discovered. Histological examination revealed adenocarcinoma, consistent with systemic recurrence of the patient's known cholangiocarcinoma.


Assuntos
Colangiocarcinoma/complicações , Neoplasias Pélvicas/complicações , Neoplasias Ureterais/complicações , Obstrução Ureteral/etiologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/secundário , Feminino , Humanos , Hidronefrose/diagnóstico por imagem , Hidronefrose/etiologia , Pessoa de Meia-Idade , Neoplasias Pélvicas/secundário , Tomografia Computadorizada por Raios X , Neoplasias Ureterais/secundário , Obstrução Ureteral/diagnóstico por imagem , Obstrução Ureteral/patologia , Urografia
3.
Life Sci ; 239: 117015, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678551

RESUMO

Obstructive renal injury and drug-induced nephrotoxicity are the two most common causes of renal fibrosis diseases. However, whether these two different pathogeny induced same pathological outcomes contain common genetic targets or signaling pathway, the current research has not paid great attention. GSE121190 and GSE35257 were downloaded from the Gene Expression Omnibus (GEO) database. While GSE121190 represents a differential expression profile in kidney of mice with unilateral ureteral obstruction (UUO) model, GSE35257 represents cisplatin nephrotoxicity model. By using GEO2R, 965 differential expression genes (DEGs) in GSE121190 and 930 DEGs in GSE35257 were identified. 43 co-DEGs were shared and were extracted for protein-protein interaction (PPI) analysis. Subsequently, three shared pathways including glycolysis/gluconeogenesis, fatty acid degradation and pathways in cancer were involved in two models with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We reconfirmed that these three pathways have relatively high scores by using Gene Set Enrichment Analysis (GSEA) software. Additionally, further bioinformatic analysis showed that Aldehyde dehydrogenase-2 (Aldh2) involved in the progression of renal fibrosis by mediating glycolysis pathway. Then real-time PCR and western blotting were performed to validate the expression of Aldh2 in kidney tissue after three different etiologies that caused renal fibrosis. Basically consistent with our bioinformatics results, our experiment showed that the expression of Aldh2 is the most significantly decreased in the UUO model, followed by ischemia-reperfusion injury (IRI) model and finally the cisplatin-induced model. Thus, Aldh2 can act as a common potential genetic target for different renal fibrosis diseases.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Nefropatias/tratamento farmacológico , Nefropatias/enzimologia , Aldeído-Desidrogenase Mitocondrial/efeitos dos fármacos , Animais , Cisplatino/toxicidade , Biologia Computacional , Bases de Dados Genéticas , Fibrose , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Nefropatias/induzido quimicamente , Nefropatias/genética , Camundongos , Camundongos Endogâmicos BALB C , Mapas de Interação de Proteínas , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/patologia
4.
Braz J Med Biol Res ; 52(11): e8772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664306

RESUMO

This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.


Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Nefropatias/patologia , Piridonas/farmacologia , Obstrução Ureteral/patologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Fator Apoptótico 1 Ativador de Proteases/efeitos dos fármacos , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Nitrogênio da Ureia Sanguínea , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Creatinina/sangue , Modelos Animais de Doenças , Enalapril/metabolismo , Enalapril/farmacologia , Proteína de Domínio de Morte Associada a Fas/efeitos dos fármacos , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibrose , Masculino , Piridonas/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Fator de Transcrição CHOP/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo
5.
Biol Res ; 52(1): 50, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492196

RESUMO

BACKGROUND: Ureteral obstruction causes injury of the renal tissues and can irreversibly progress to renal fibrosis, with atrophy and apoptosis of tubular cells. The goal of the current study was to examine the effects of rhein on the apoptosis o renal tubular cells as well as renal fibrosis using a rodent model of unilateral ureteral obstruction (UUO). METHODS: UUO was induced through ureteral ligation, then animals received treatments with rhein or vehicle. The control rats only received sham operation. The renal tissue was harvested 1 week after surgery for assessment of kidney fibrosis. RESULTS: The expressions of collagen I and α-smooth muscle actin (α-SMA), as well as the severity of renal tubular apoptosis and fibrosis were time-dependently increased following UUO. Treatments with rhein partially inhibited such responses. Renal interstitial fibrosis was associated with STAT3 (signal transducer and activator of transcription 3) phosphorylation as well as altered expressions of Bax and Bcl2, both apoptosis-related proteins. Treatment with rhein also partly blocked these responses. CONCLUSION: These findings demonstrated that rhein mitigated apoptosis of renal tubular cell as well as renal fibrosis in a UUO rodent model. This curative effect is likely mediated via suppression of STAT3 phosphorylation.


Assuntos
Antraquinonas/administração & dosagem , Apoptose/efeitos dos fármacos , Rim/patologia , Obstrução Ureteral/prevenção & controle , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
6.
Exp Mol Pathol ; 111: 104296, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31449784

RESUMO

BACKGROUND: Nrf2 constitutes a therapeutic reference point for renal fibrosis and chronic kidney diseases. Nrf2-related signaling pathways are recognized to temper endothelial-to-mesenchymal transition (EMT) in fibrotic tissue. Nevertheless, the mechanism by which Nrf2 mitigates renal interstitial fibrosis is imprecise. METHODS: The relationship between Nrf2 and renal interstitial fibrosis was investigated using the unilateral ureteral obstruction (UUO) model of Nrf2-/- mice. The mice were separated into four groups, based on the treatment and intervention: Nrf2-/- + UUO, Nrf2-/- + Sham, WT + UUO and WT + Sham. Histological examination of renal tissue following the hematoxylin-eosin and Masson staining was carried out, as well as immunohistochemical staining. Additionally, to confirm the in vivo discoveries, in vitro experiments with HK-2 cells were also performed. RESULTS: The Nrf2-/- + UUO group showed more severe renal interstitial fibrosis compared to the WT + UUO, Nrf2-/- + Sham and WT + Sham groups. Furthermore, the manifestations of α-SMA and Fibronectin significantly increased, and the manifestation of E-cadherin considerably decreased in kidney tissues from the group of Nrf2-/- + UUO, compared to the WT + UUO group. The Nrf2 protein level significantly decreased in HK-2 cells, in reaction to the TGF-ß1 concentration. In addition, the overexpression of Nrf2 presented contradictory results. What is more, the PI3K/Akt signaling pathway was discovered to be activated in the proteins extracted from cultured cells, and treated with Nrf2 siRNA and kidney tissues from the Nrf2-/- + UUO group. CONCLUSIONS: The results we obtained demonstrate that Nrf2 signaling pathway may perhaps offset the development of EMT, prompted by TGF-ß1 and renal interstitial fibrosis. Likewise, the anti-fibrotic effect of Nrf2 was imparted by the inactivation of PI3K/Akt signaling. From our discoveries, we deliver new insight related to the prevention and treatment of kidney fibrosis.


Assuntos
Transição Epitelial-Mesenquimal , Fibrose/prevenção & controle , Nefropatias/prevenção & controle , Fator 2 Relacionado a NF-E2/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Obstrução Ureteral/prevenção & controle , Animais , Caderinas/genética , Caderinas/metabolismo , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/etiologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
7.
BMC Urol ; 19(1): 80, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464587

RESUMO

BACKGROUND: The aim of this study was to examine ureteral stricture rate after the use of UAS in an unstented ureter and compare complications of smaller vs. larger-caliber UAS. METHODS: We conducted a retrospective analysis of consecutive RIRS for renal stones, with the use of UAS in unstented ureters. We excluded cases with previous ureteroscopies, who carried ureteral stent or nephrostomy, had impacted stones, underwent radiation treatment, or had urinary tract malignancies. The primary outcome was formation of ureteral strictures diagnosed by hydronephrosis in ultrasound test and late secretion in dynamic renal scan. Secondary outcome was stone-free-rate (SFR) and complications. In addition, we compared safety and efficacy of smaller (9.5/11.5Fr) vs. larger-caliber (12/14Fr) UAS. RESULTS: The cohort included 165 patients with a median follow-up time of 115 days. There was no case of ureteral stricture formation after the use us UAS, despite using a larger-caliber UAS in nearly half the cases. Larger-caliber UAS was not associated with more complications compared to the smaller-caliber one (p = 0.780). SFR was non-significantly higher in the larger-caliber UAS group (p = 0.056), despite having a larger stone burden, and only stone number was associated with SFR (p = 0.003). CONCLUSIONS: These data suggest that the use of UAS during RIRS in an unstented ureter is safe and does not involve ureteral stricture formation after one procedure. Furthermore, the use of wider sheaths was not found to be associated with higher complications rate.


Assuntos
Cálculos Renais/cirurgia , Complicações Pós-Operatórias/etiologia , Obstrução Ureteral/etiologia , Procedimentos Cirúrgicos Urológicos/instrumentação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Constrição Patológica , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Ureter , Obstrução Ureteral/epidemiologia , Obstrução Ureteral/patologia , Adulto Jovem
8.
Nephrology (Carlton) ; 24(9): 983-991, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31314137

RESUMO

AIM: Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C-C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-ß1 (TGF-ß1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. METHODS: Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2-/- and wild type (WT) littermate mice which were killed 7 days later. Non-experimental mice were controls. RESULTS: Wild type mice exhibited a 5-fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM-1 and decreased α-Klotho expression) and tubular signalling (extracellular signal-regulated kinase phosphorylation) seen in WT UUO were not altered in Par2-/- UUO. In addition, macrophage infiltration, up-regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up-regulation of pro-inflammatory molecules (tumour necrosis factor, CCL2, interleukin-36α) in WT UUO kidney were unchanged in Par2-/- UUO. Finally, the accumulation of α-SMA+ myofibroblasts, deposition of collagen IV and expression of pro-fibrotic factors (CTGF, TGF-ß1) were not different between WT and Par2-/- UUO mice. CONCLUSION: Protease-activated receptor 2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.


Assuntos
Túbulos Renais/metabolismo , Nefrite Intersticial/etiologia , Receptor PAR-2/metabolismo , Obstrução Ureteral/complicações , Animais , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite Intersticial/genética , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Receptor PAR-2/deficiência , Receptor PAR-2/genética , Transdução de Sinais , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
9.
Life Sci ; 232: 116609, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254585

RESUMO

Pioglitazone has been demonstrated to exert anti-fibrotic and renoprotective effects. But the detailed pharmacological mechanisms have not been clearly revealed. The present study aimed to investigate the possible mechanisms of pioglitazone in these two effects. TGF-ß1-stimulated HK-2 cells and unilateral ureteral obstruction (UUO) mice were used as in vitro and in vivo models. The results showed that pioglitazone inhibited Smad-2/3 phosphorylation, upregulated Smad-7 expression and downregulated miR-21-5p expression in TGF-ß1-exposed HK-2 cells. In addition, miR-21-5p inhibitors replicated the anti-fibrotic effects of pioglitazone, and miR-21-5p mimics inhibited these effects. In in vivo study, pioglitazone attenuated UUO-induced renal fibrosis and significantly decreased the expressions of pro-fibrotic proteins. Whereas, agomir of miR-21-5p inhibited the renoprotective function of pioglitazone in UUO mice. In conclusion, the present data suggest that modulation of miR-21-5p/Smad-7 signal may be involved in the anti-fibrotic effect of pioglitazone in the kidney of UUO mice.


Assuntos
Rim/efeitos dos fármacos , Rim/patologia , MicroRNAs/metabolismo , Pioglitazona/farmacologia , Animais , Linhagem Celular , Fibrose/induzido quimicamente , Fibrose/genética , Células HEK293 , Humanos , Rim/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/patologia
10.
Redox Biol ; 26: 101234, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31247506

RESUMO

BACKGROUND: NADPH oxidase 4 (NOX4) catalyzes the formation of hydrogen peroxide (H2O2). NOX4 is highly expressed in the kidney, but its role in renal injury is unclear and may depend on its specific tissue localization. METHODS: We performed immunostaining with a specific anti-NOX4 antibody and measured NOX4 mRNA expression in human renal biopsies encompassing diverse renal diseases. We generated transgenic mice specifically overexpressing mouse Nox4 in renal tubular cells and subjected the animals to the unilateral ureteral obstruction (UUO) model of fibrosis. RESULTS: In normal human kidney, NOX4 protein expression was at its highest on the basolateral side of proximal tubular cells. NOX4 expression increased in mesangial cells and podocytes in proliferative diabetic nephropathy. In tubular cells, NOX4 protein expression decreased in all types of chronic renal disease studied. This finding was substantiated by decreased NOX4 mRNA expression in the tubulo-interstitial compartment in a repository of 175 human renal biopsies. Overexpression of tubular NOX4 in mice resulted in enhanced renal production of H2O2, increased NRF2 protein expression and decreased glomerular filtration, likely via stimulation of the tubulo-glomerular feedback. Tubular NOX4 overexpression had no obvious impact on kidney morphology, apoptosis, or fibrosis at baseline. Under acute and chronic tubular injury induced by UUO, overexpression of NOX4 in tubular cells did not modify the course of the disease. CONCLUSIONS: NOX4 expression was decreased in tubular cells in all types of CKD tested. Tubular NOX4 overexpression did not induce injury in the kidney, and neither modified microvascularization, nor kidney structural lesions in fibrosis.


Assuntos
Nefropatias Diabéticas/genética , NADPH Oxidase 4/genética , RNA Mensageiro/genética , Insuficiência Renal Crônica/genética , Obstrução Ureteral/genética , Animais , Biópsia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Peróxido de Hidrogênio/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos , Camundongos Transgênicos , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Podócitos/metabolismo , Podócitos/patologia , RNA Mensageiro/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
11.
Biofactors ; 45(5): 750-762, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31188510

RESUMO

Chronic kidney disease (CKD) is one of the major global health concerns and is responsible for end-stage renal disease (ESRD) complications. Inflammation plays a pivotal role in the progression of CKD. In the present study, we evaluated the renoprotective effects of a potent immunomodulator steroidal lactone, Withaferin A (WfA), in an animal model of renal injury (unilateral ureteral obstruction, UUO) and further investigated if the inhibition of inflammatory signaling can be a useful approach to reduce renal injury. Animals were randomly divided into five groups: Sham control, UUO control, WfA control, WfA low dose (1 mg/kg), and WfA high dose (3 mg/kg). Oxidative stress was measured by the estimation of reduced glutathione and lipid peroxidation levels. H&E and Picrosirius Red staining were performed to assess the extent of histological damage and collagen deposition. Furthermore, the molecular mechanism of the WfA effects was explored by immunohistochemistry, enzyme-linked immunosorbent assay, multiplex analysis of transforming growth factor ß (TGF-ß) pathway, and an array of inflammatory cytokines/chemokines. Interestingly, our pharmacological intervention significantly attenuated tissue collagen, inflammatory signaling, and macrophage signaling. WfA intervention abrogated the inflammatory signaling as evident from the modulated levels of chemokines and cytokines. The levels of TGF-ß along with downstream signaling molecules were also attenuated by WfA treatment as revealed by inhibition in the expression of TGF-ß1, TGF-ß2, p-Smad2, p-Smad3, total Smad4, p-Akt, and p-ERK. We, to the best of our knowledge, prove for the first time that WfA has potential renoprotective activity against UUO-induced nephropathy due to its outstanding anti-inflammatory properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/tratamento farmacológico , Vitanolídeos/farmacologia , Animais , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutationa/agonistas , Glutationa/metabolismo , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Resultado do Tratamento , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
12.
Mol Med Rep ; 20(2): 1353-1362, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173201

RESUMO

Chronic kidney disease is the outcome of most kidney diseases, and renal fibrosis is a pathological process involved in the progression of these disorders. The role of interleukin (IL)­33 was previously investigated in fibrotic disorders affecting various organs, including liver, lungs and heart; however, its role in renal fibrosis remains unclear. Previous studies have demonstrated that macrophages are involved in obstructive renal injury. In the present study, the roles of IL­33 and macrophages on renal fibrosis were investigated using a mouse model of unilateral ureteral obstruction (UUO). Compared with non­obstructed kidneys, the expression levels of IL­33 and its receptor, interleukin 1 receptor like 1, increased after UUO. Furthermore, the infiltration of macrophages and the degree of renal fibrosis increased after treatment with IL­33. Additionally, the expression level of arginase­1, a marker of M2 macrophages, increased in renal tissue. After depletion of macrophages, the administration of exogenous IL­33 was not sufficient to reverse the reduction in fibrosis caused by elimination of these cells. Collectively, the present results suggested that IL­33 promoted renal fibrosis in UUO­induced renal injury by regulating macrophage polarization.


Assuntos
Interleucina-33/metabolismo , Rim/lesões , Rim/patologia , Macrófagos/patologia , Animais , Polaridade Celular , Modelos Animais de Doenças , Fibrose , Inflamação/patologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-13/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas Recombinantes/efeitos adversos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
13.
Hum Cell ; 32(3): 297-305, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054069

RESUMO

Renal fibrosis is the major feature of end-stage renal disease with high mortality. Chloride (Cl-) moving along Cl- channels has been suggested to play to an important role in renal function. This study aims to investigate the role of ClC-5 in renal fibrosis in unilateral ureteral occlusion (UUO) mice. C57BL/6 mice received UUO surgery followed by delivery of adeno-associated virus encoding ClC-5 cDNA (AAVClC-5). Western blotting, real-time PCR and histological analysis were used to investigate the effects of ClC-5 on renal fibrosis and underlying mechanisms. The expression of ClC-5 was significantly decreased in renal cortex of UUO mice and transforming growth factor-ß1 (TGF-ß1)-stimulated HK2 cells. Overexpression of ClC-5 in vivo markedly ameliorated UUO-induced renal injury and fibrosis. The increased expressions of plasminogen activator inhibitor type 1, connective tissue growth factor, collagen III and collagen IV were also inhibited by ClC-5 upregulation. Moreover, UUO-induced immune cell infiltration and inflammatory cytokines release were attenuated in mice infected with AAVClC-5. In addition, the in vivo and in vitro results showed that ClC-5 overexpression prevented epithelial-to-mesenchymal transition (EMT), concomitantly with a restoration of E-cadherin expression and a decrease of vimentin, α-SMA and S100A4 expressions. Furthermore, ClC-5 overexpression inhibited UUO- or TGF-ß1-induced increase in nuclear factor kappa B (NF-κB) acetylation and matrix metalloproteinases-9 (MMP-9) expression. However, downregulation of ClC-5 in HK2 cells further potentiated TGF-ß1-induced EMT and increase in NF-κB acetylation and MMP-9 expression. ClC-5 upregulation ameliorates renal fibrosis via inhibiting NF-κB/MMP-9 pathway signaling activation, suggesting that ClC-5 may be a novel therapeutic target for treating renal fibrosis and chronic kidney disease.


Assuntos
Canais de Cloreto/genética , Canais de Cloreto/fisiologia , Expressão Gênica , Rim/metabolismo , Rim/patologia , Regulação para Cima , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , Animais , Caderinas/metabolismo , Células Cultivadas , Canais de Cloreto/metabolismo , Canais de Cloreto/uso terapêutico , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Fibrose , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , NF-kappa B/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/tratamento farmacológico
14.
Cell Physiol Biochem ; 52(6): 1484-1502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099508

RESUMO

BACKGROUND/AIMS: The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys. METHODS: Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR. RESULTS: Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO. CONCLUSION: TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions.


Assuntos
Regulação da Expressão Gênica , Rim/patologia , Canais de Cátion TRPC/genética , Obstrução Ureteral/genética , Animais , Modelos Animais de Doenças , Fibrose , Deleção de Genes , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , RNA Mensageiro/análise , RNA Mensageiro/genética , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Regulação para Cima , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia
15.
Turk J Med Sci ; 49(2): 696-702, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30997983

RESUMO

Background/aim: The aim was to investigate the protective and therapeutic effects of ghrelin, which has antioxidant and antiinflammatory activity, on preventing kidney damage that occurs by induced partial ureteral obstruction in rats Materials and methods: Twenty-eight adult male rats were included in the study, and the rats were divided into 4 groups. After the laparotomy operation on the sham group, the ureter was identified in the retroperitoneal area and was duly sutured (n = 7). Ghrelin was administered for seven days intraperitoneally, and after the nephrectomy performed on the 15th day, the rats were sacrificed (n = 7). A partial ureteral obstruction was performed after the laparotomy on the PUO group. The rats were sacrificed after the nephrectomy operation performed on the 15th day (n = 7). A partial ureteral obstruction was formed after the laparotomy followed by seven days of waiting in the PUO + ghrelin group. Ghrelin was given in the dose of 10 ng/kg per day intraperitoneally for the next 7 days, and the rats were sacrificed after the nephrectomy operation performed on the 15th day (n = 7). All groups were evaluated for histological damage and catalase, superoxide dismutase, total glutathione, malondialdehyde, and myeloperoxidase levels were measured in the same tissues Results: When the 2nd group and the sham group were compared histologically, it was observed that the damage had increased by a statistically significant level in the partial ureteral obstruction group (P = 0.001). When the group which was ghrelin-treated after the partial ureteral obstruction was compared to the group with just partial ureteral obstruction, the histopathological changes were found to decrease significantly in that group (P = 0.001). While the statistical significance of the levels of CAT, GSH, and MPO enzymes was detected among biochemical changes in the 2nd group when compared to the sham group (P < 0.01), the 3rd group showed a statistically significant difference in the levels of SOD and GSH enzymes compared to the 4th group (P < 0.05). Conclusion: Ghrelin administration to rats after the formation of an experimental partial unilateral ureteral obstruction reduces tissue damage due to ghrelin's antiinflammatory and antioxidant effects. Ghrelin administration may prevent tissue damage biochemically and histopathologically in obstructive uropathy cases


Assuntos
Anti-Inflamatórios/farmacologia , Grelina/farmacologia , Nefropatias/patologia , Rim/patologia , Substâncias Protetoras/farmacologia , Obstrução Ureteral/patologia , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/farmacologia , Modelos Animais de Doenças , Grelina/administração & dosagem , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Masculino , Ratos , Ureter/patologia , Obstrução Ureteral/complicações
16.
Rev Assoc Med Bras (1992) ; 65(3): 388-393, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30994838

RESUMO

OBJECTIVES: We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO). METHODS: The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T). RESULTS: Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss.The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-ß (TGF-ß) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-ß decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T. CONCLUSION: The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-ß in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.


Assuntos
Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia , Actinas/análise , Animais , Ensaio de Imunoadsorção Enzimática , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Fator de Crescimento Transformador beta/análise , Regulação para Cima , Ureter/efeitos dos fármacos , Ureter/patologia
17.
Biomolecules ; 9(4)2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965656

RESUMO

Renal fibrosis is the common pathway for most forms of progressive renal disease. The Unilateral Ureteral Obstruction (UUO) model is used to cause renal fibrosis, where the primary feature of UUO is tubular injury as a result of obstructed urine flow. Furthermore, experimental UUO in rodents is believed to mimic human chronic obstructive nephropathy in an accelerated manner. Renal fibrosis is the common pathway for most forms of progressive renal disease. Removing the obstruction may not be sufficient to reverse fibrosis, so an accompanying treatment may be of benefit. In this review, we have done a revision on treatments shown to ameliorate fibrosis in the context of the UUO experimental model. The treatments inhibit the production of fibrotic and inflammatory proteins such as Transforming Growth Factor ß1 (TGF-ß1), Tumor Necrosis Factor α (TNF-α), collagen and fibronectin, Heat Shock Protein 47 (HSP47), suppress the proliferation of fibroblasts, prevent epithelial-to-mesenchymal transition, reduce oxidative stress, inhibit the action of the Nuclear Factor κB (NF-κB), reduce the phosphorylation of mothers against decapentaplegic homolog (SMAD) family members 2 and 3 (Smad2/3) or Mitogen-Activated Protein Kinases (MAPKs), inhibit the activation of the renin-angiotensin system. Summaries of the UUO experimental methods and alterations observed in the UUO experiments are included.


Assuntos
Fibrose/tratamento farmacológico , Modelos Biológicos , Obstrução Ureteral/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Fibrose/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Obstrução Ureteral/patologia
18.
Life Sci ; 223: 29-37, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30862567

RESUMO

AIMS: Renal fibrosis is the most common final stage of progressive renal disease, characterized by fibroblast proliferation, fibroblast-to-myofibroblast differentiation and excessive accumulation of extracellular matrix. Dihydroartemisinin (DHA) exerts antitumor, antibacterial, and antifibrotic effects. The aim of this study was to determine whether DHA has beneficial effects on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice and to examine explore the underlying possible mechanisms. MATERIALS AND METHODS: Eight-week-old male C57BL/6 mice were intragastrically administered DHA for 14 consecutive days after UUO operation. Afterward, interstitial collagen deposition, expression of collagen I and III, fibronectin, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and S100 calcium-binding protein A4 (S100A4) were assessed in the kidneys. Transforming growth factor beta 1 (TGF-ß1)-induced primary human kidney fibroblasts were treated with DHA to further investigate the mechanism underlying its action. KEY FINDINGS: In vivo, DHA reduced UUO-induced morphological and pathological changes and the degree of renal fibrosis. In addition, DHA mitigated fibroblast proliferation and differentiation in kidney tissue induced by UUO. In vitro, DHA significantly attenuated the TGF-ß1-induced primary human kidney fibroblast proliferation and fibroblast-to-myofibroblast differentiation. Moreover, treatment with DHA attenuated the up-regulation of phosphorylation of phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) in UUO model and TGF-ß1-induced primary human kidney fibroblasts. SIGNIFICANCE: We provide in vivo and in vitro evidence that DHA may relieve renal fibrosis through regulation of fibroblast proliferation and differentiation by mitigating the PI3K/AKT pathway. DHA may potentially be used as a therapeutic antifibrotic agent for the treatment of renal fibrosis.


Assuntos
Artemisininas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Rim , Obstrução Ureteral/patologia , Animais , Modelos Animais de Doenças , Fibroblastos/patologia , Fibrose , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
PLoS One ; 14(2): e0202842, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818366

RESUMO

Leukotriene B4 (LTB4) is a lipid mediator that acts as a potent chemoattractant for inflammatory leukocytes. Kidney fibrosis is caused by migrating inflammatory cells and kidney-resident cells. Here, we examined the role of the high-affinity LTB4 receptor BLT1 during development of kidney fibrosis induced by unilateral ureteral obstruction (UUO) in wild-type (WT) mice and BLT1 knockout (BLT1-/-) mice. We found elevated expression of 5-lipoxygenase (5-LOX), which generates LTB4, in the renal tubules of UUO kidneys from WT mice and BLT1-/- mice. Accumulation of immunoreactive type I collagen in WT UUO kidneys increased over time; however, the increase was less prominent in BLT1-/- UUO kidneys. Accumulation of S100A4-positive fibroblasts increased temporally in WT UUO kidneys, but was again less pronounced in-BLT1-/- UUO kidneys. The same was true of mRNA encoding transforming growth factor-ß (TGF)-ß and fibroblast growth factor (FGF)-2. Finally, accumulation of F4/80-positive macrophages, which secrete TGF-ß, increased temporally in WT UUO and BLT1-/- UUO kidneys, but to a lesser extent in the latter. Following LTB4 stimulation in vitro, macrophages showed increased expression of mRNA encoding TGF-ß/FGF-2 and Col1a1, whereas L929 fibroblasts showed increased expression of mRNA encoding α smooth muscle actin (SMA). Bone marrow (BM) transplantation studies revealed that the area positive for type I collagen was significantly smaller in BLT1-/-BM→WT than in WT-BM→WT. Thus, LTB4-BLT1 signaling plays a critical role in fibrosis in UUO kidneys by increasing accumulation of macrophages and fibroblasts. Therefore, blocking BLT1 may prevent renal fibrosis.


Assuntos
Receptores do Leucotrieno B4/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Animais , Apoptose/fisiologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/metabolismo , Rim/metabolismo , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores do Leucotrieno B4/genética , Transdução de Sinais , Obstrução Ureteral/patologia
20.
Phytomedicine ; 57: 223-235, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30785018

RESUMO

BACKGROUND: Renal fibrosis is the pathological feature of chronic kidney disease (CKD) which leads to end-stage renal disease (ESRD) and renal failure. Resveratrol [3,5,4'-trihydroxy-trans-stilbene (RSV)] has shown benefits for metabolic diseases and anti-cancer therapy, but its potential risk on renal health has not been fully evaluated. PURPOSE: To investigate the global effects of RSV on renal fibrosis in human tubular epithelial cell (TEC) line HK-2, and in mice with unilateral ureteral obstruction (UUO). METHODS: A TGF-ß-induced in vitro model of epithelial-mesenchymal transition (EMT) in TEC was established. The effects of RSV on cell viability, pro-fibrotic factors, oxidative stress, mitochondria function, and underlying pathway proteins were analyzed. In vivo, the effects of RSV on renal function and fibrosis were assayed in UUO mice. RESULTS: Our results showed that low concentrations of RSV (5-20 µM) decreased TGF-ß-induced EMT via Sirt1-dependent deacetylation of Smad3/Smad4 mechanism. By contrast, long-term (72 h) exposure to high concentrations of RSV (≥ 40 µM) promoted EMT in HK-2 cells via mitochondrial oxidative stress and ROCK1-mediated disordered cytoskeleton remodeling. In vivo, low-dose treatment of RSV (≤ 25 mg/kg) partly improved renal function, whereas high-dose treatment of RSV (≥ 50 mg/kg) lost its anti-fibrotic role and even aggravated renal fibrosis. However, mice with UUO were more susceptible to high RSV-induced renal injury than normal mice. CONCLUSION: Dependent on dose, RSV activated either anti-fibrotic or pro-fibrotic effects in kidneys. The risk of RSV consumption in individuals with impaired kidney function should be carefully considered.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Resveratrol/administração & dosagem , Resveratrol/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Fibrose/patologia , Humanos , Rim/patologia , Rim/fisiopatologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Sirtuína 1/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/toxicidade , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA