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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.
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
3.
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
4.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295865

RESUMO

G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic ß-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway.


Assuntos
Lesão Renal Aguda/metabolismo , Apoptose/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Apoptose/genética , Biomarcadores , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Imuno-Histoquímica , Túbulos Renais Proximais/patologia , Masculino , Ratos , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo
5.
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
6.
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
7.
PLoS One ; 14(6): e0218986, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31251767

RESUMO

In unilateral ureteral obstruction (UUO), both oxidative stress and mitochondrial dysfunction are related to cell death. The aim of this study has been to characterize profiles of enzyme antioxidant activities and mitochondrial functioning of the contralateral (CL) compared to UUO and Sham (false-operated) kidneys of Balb/c mice. Kidneys were resected 14 days after obstruction for immunohistochemical and cortical mitochondrial functioning assays. Antioxidant enzymes activities were investigated in mitochondria and cytosol. Oxygen consumption (QO2) and formation of O2 reactive species (ROS) were assessed with pyruvate plus malate or succinate as the respiratory substrates. QO2 decreased in CL and UUO in all states using substrates for complex II, whereas it was affected only in UUO when substrates for complex I were used. Progressive decrease in mitochondrial ROS formation-in the forward and reverse pathway at complex I-correlates well with the inhibition of QO2 and, therefore, with decreased electron transfer at the level of complexes upstream of cytochrome c oxidase. CL and UUO transmembrane potential responses to ADP were impaired with succinate. Intense Ca2+-induced swelling was elicited in CL and UUO mitochondria. Important and selective differences exist in CL antioxidant enzymes with respect to either Sham or UUO kidneys: CL kidneys had increased mitochondrial glutathione peroxidase and cytosolic catalase activities, indicative of compensatory responses in the face of an early altered ROS homeostasis (as detected by 4-hydroxynonenal), and of a significant tendency to apoptosis. In CL and UUO, upregulation of nuclear (erythroid-derived 2)-like 2 transcription factor (Nrf2), as well as of cytoplasmic and nuclear Kelch-like ECH-associated protein 1 (Keap1) in opposition to decreased heme oxygenase-1 (HO-1), suggest impairment of the Nrf2/Keap1/HO-1 system. It is concluded that chronic obstruction impairs mitochondrial function in CL and UUO, preferentially affecting complex II.


Assuntos
Rim/citologia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Obstrução Ureteral/cirurgia , Animais , Sinalização do Cálcio , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Homeostase , Rim/metabolismo , Rim/cirurgia , Masculino , Camundongos , Oxirredução , Regulação para Cima , Obstrução Ureteral/etiologia , Obstrução Ureteral/metabolismo
8.
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
9.
Mol Immunol ; 112: 247-255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202101

RESUMO

Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-ß (TGF-ß) plays a pivotal role in progression of renal fibrosis. TGF-ß transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-ß, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-ß, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.


Assuntos
Fibrose/tratamento farmacológico , Limoninas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/fisiopatologia , Animais , Transição Epitelial-Mesenquimal , Fibrose/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/metabolismo
10.
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
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(2): 156-161, 2019 02 28.
Artigo em Chinês | MEDLINE | ID: mdl-30890502

RESUMO

OBJECTIVE: To explore the effect of telmisartan on the expression of metadherin in the kidney of mice with unilateral ureter obstruction. METHODS: Eighteen male C57 mice were randomized into sham-operated group, model group and telmisartan treatment group. In the latter two groups, renal interstitial fibrosis as the result of unilateral ureter obstruction (UUO) was induced by unilateral ureteral ligation with or without telmisartan intervention. Renal pathological changes of the mice were assessed using Masson staining, and immunohistochemistry and Western blotting were used to detect the expression of extracellular matrix proteins and metadherin in the kidney of the mice. In the in vitro experiment, cultured mouse renal tubular epithelial cells (mTECs) were stimulated with transforming growth factor-ß1 (TGF-ß1) and transfected with a siRNA targeting metadherin, and the changes in the expressions of extracellular matrix proteins and metadherin were detected using Western blotting. RESULTS: The expressions of extracellular matrix proteins and metadherin increased significantly in the kidney of mice with UUO (P < 0.05). Intervention with telmisartan significantly lowered the expressions of extracellular matrix proteins and metadherin and alleviated the pathology of renal fibrosis in mice with UUO (P < 0.05). In cultured mTECs, siRNA-mediated knockdown of metadherin obviously reversed TGF-ß1-induced increase in the expressions of extracellular matrix proteins and metadherin. CONCLUSIONS: Telmisartan can suppress the production of extracellular matrix proteins and the expression of metadhein to attenuate UUO-induced renal fibrosis in mice.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Rim/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Telmisartan/farmacologia , Obstrução Ureteral/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Anti-Hipertensivos , Fibrose , Rim/metabolismo , Rim/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Distribuição Aleatória , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/complicações
12.
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
13.
Phytomedicine ; 53: 274-285, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668407

RESUMO

BACKGROUND: Renal fibrosis is the most common pathway leading to end-stage renal disease. It is characterized by excess extracellular matrix (ECM) accumulation and renal tissue damage, subsequently leading to kidney failure. Asperulosidic acid (ASPA), a bioactive iridoid glycoside, exerts anti-tumor, anti-oxidant, and anti-inflammatory activities, but its effects on renal fibrosis induced by unilateral ureteral obstruction (UUO) have not yet been investigated. PURPOSE: This study aimed to investigate the protective effect of ASPA on renal fibrosis induced by UUO, and to explore its pharmacological mechanism. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: sham group, UUO model group, three ASPA treatment groups (10, 20, and 40 mg/kg), and captopril group (20 mg/kg). Rats were administered vehicle, ASPA or captopril intraperitoneally once a day for 14 consecutive days. Urea nitrogen (BUN), uric acid (UA) and inflammatory factors in serum samples were evaluated on the 7th, 10th, and 14th day after renal fibrosis induction. In addition, the 12 h urine was collected to test the content of urinary protein (upro) on the 14th day. The obstructive renal tissues were collected for pathological analysis (hematoxylin and eosion (H&E) staining and Masson's Trichrome staining) and immunohistochemical analysis on the 14th day after renal fibrosis induction. The mRNA expression of related factors and the protein levels of smad2, smad3, and smad4 were measured in UUO-induced rats by real time PCR and Western blot, respectively. RESULTS: The levels of BUN, UA, and upro were elevated in UUO-induced rats, but ASPA treatment improved renal function by reducing the levels of BUN, UA, and upro. The protein levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6, as well as the mRNA levels of TNF-α, IL-1ß, IL-6, monocyte chemoattractant protein-1 (MCP-1) and interferon-γ (IFN-γ), were decreased after ASPA administration (10, 20 and 40 mg/kg) in a dose-dependent manner. The ASPA exerted an alleviation effect on the inflammatory response through inhibition of nuclear factor-kappa B (NF-κB) pathway. In addition, reductions in α-smooth muscle actin (α-SMA), collagen III, and fibronectin expression were observed after ASPA administration at doses of 20 and 40 mg/kg. Furthermore, the renal expression of transforming growth factor-ß1 (TGF-ß1), smad2, smad3, and smad4 was down-regulated by ASPA treatment at doses of 20 and 40 mg/kg. CONCLUSION: ASPA possessed protective effects on renal interstitial fibrosis in UUO-induced rats. These effects may be through inhibition of the activation of NF-κB and TGF-ß1/smad2/smad3 signaling pathways.


Assuntos
Fibrose/tratamento farmacológico , Glicosídeos/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Obstrução Ureteral/tratamento farmacológico , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Fibrose/patologia , Glicosídeos/administração & dosagem , Rim/patologia , Nefropatias/tratamento farmacológico , Masculino , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismo
14.
Biomolecules ; 9(1)2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641998

RESUMO

Arabic gum (AG) has antioxidant and anti-inflammatory properties. However, the effect of AG in ureteric obstruction (UO) has not been investigated yet. Male rats underwent reversible left unilateral UO (UUO) for 72 h. Group AG-1 (n = 12) received AG 15 g/kg/day dissolved in drinking water starting seven days before and continuing throughout the period of the UUO, whereas group Vx-1 (n = 8) had only water. Group AG-2 (n = 12) and Vx-2 (n = 8) had similar protocols as AG-1 and Vx-1, respectively, but underwent terminal experiments to measure renal functions, six days post-UUO reversal. Arabic gum significantly attenuated the UUO-induced increase in the tissue level of malonedialdehyde and superoxide dismutase and the rise in the gene expression of TNF-α, TGF-ß1, and p53 in AG-1 compared to Vx-1. It also attenuated the severity of tubular dilatation. However, AG did not affect the alterations in the renal blood flow or glomerular filtration rate. The fractional sodium excretion was lower in AG-2 but did not reach statistical significance (0.40 ± 0.11 vs 0.74 ± 0.12, p = 0.07). AG attenuated the UUO-induced rise in oxidative stress markers and proinflammatory and profibrotic cytokines and the degree of renal tubular dilatation, indicating a protective effect in obstructive nephropathy.


Assuntos
Antioxidantes/farmacologia , Goma Arábica/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Obstrução Ureteral/patologia , Animais , Antioxidantes/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Taxa de Filtração Glomerular , Goma Arábica/uso terapêutico , Rim/metabolismo , Rim/patologia , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo
15.
Nephrology (Carlton) ; 24(4): 472-480, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29717517

RESUMO

AIM: To understand the mechanism of long non-coding RNA (LncRNA) HOTAIR on renal interstitial fibrosis (RIF) by regulating Notch1 pathway via the modulation of miR-124. METHODS: Unilateral ureteral occlusion (UUO) was used to construct the RIF rat model. HK-2 cells induced by TGF-ß1 were used for the in vitro experiment, which were divided into five groups: Vehicle, TGF-ß1, si-HOTAIR+TGF-ß1, miR-124 inhibitor+TGF-ß1, and si-HOTAIR+miR-124 inhibitor+TGF-ß1 groups. Quantitative real-time PCR (qRT-PCR) and Western blot were performed to detect the expression of HOTAIR, miR-124, Notch1- and epithelial-to-mesenchymal transition (EMT)-related proteins. RESULTS: Significant elevated HOTAIR and reduced miR-124 were presented in UUO rats and TGF-ß1-induced HK-2 cells in a time-dependent manner, with the increased Jagged1 (JAG1), Notch1, NICD, α-SMA and FN, as well as the decreased E-cadherin (all P < 0.05). Compared with the TGF-ß1 group, cells in the si-HOTAIR+TGF-ß1 group were remarkably declined in cell proliferation and the protein expressions of JAG1, Notch1, NICD, α-SMA, and FN, but dramatically higher in E-cadherin expression (all P < 0.05). However, in comparison with the si-HOTAIR+TGF-ß1 group, cells in the si-HOTAIR+miR-124 inhibitor+TGF-ß1 group were apparently improved in proliferation and the protein expression of JAG1, Notch1, NICD, α-SMA, and FN, but substantially reduced in the level of E-cadherin protein (all P < 0.05). CONCLUSION: Silencing lncRNA HOTAIR can up-regulate miR-124 to block Notch1 pathway, and thereby alleviating EMT and RIF, indicating HOTAIR as a potential target for RIF treatment.


Assuntos
Nefropatias/metabolismo , Túbulos Renais Proximais/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Receptor Notch1/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Fibrose , Regulação da Expressão Gênica , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Nefropatias/genética , Nefropatias/patologia , Nefropatias/prevenção & controle , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Masculino , MicroRNAs/genética , RNA Longo não Codificante/genética , Ratos Sprague-Dawley , Receptor Notch1/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
16.
Nephrol Dial Transplant ; 34(2): 242-252, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29788096

RESUMO

Background: Sodium-potassium adenosine triphosphatase (Na/K-ATPase) has been shown to regulate Src activity by combining with Src to keep it in an inactive form. We previously reported that Na/K-ATPase was downregulated in unilateral ureteral obstruction (UUO) animals. In this study, we examined whether inhibition of Na/K-ATPase-mediated Src signaling pathways ameliorated renal interstitial fibrosis induced by UUO. Methods: UUO was performed on male C57BL/6J mice. pNaKtide, a mimic of Na/K-ATPase, was administered by intraperitoneal injection on Day 0 and Day 4 after ureteral ligation. Markers of interstitial fibrosis, inflammation and oxidative stress and transforming growth factor-ß1 (TGF-ß1) expression were examined after the mice were sacrificed on Day 7. Activation of Src and its downstream signaling effectors, including extracellular regulated protein kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (AKT), were evaluated. Results: pNaKtide administration markedly attenuated myofibroblast accumulation and extracellular matrix deposition in obstructed kidneys. Also, pNaKtide significantly reduced the increased expression of 8-iso-prostaglandin F2α, TGF-ß1, interleukin-6 and monocyte chemoattractant protein-1 (MCP-1), as well as reduced macrophage infiltration, in UUO animals. All these changes were obtained, along with inhibition of Src and its downstream effector activity. Conclusions: Na/K-ATPase-mediated signaling pathways contribute to fibrogenesis and could represent a potential target in the treatment of renal fibrosis.


Assuntos
Nefropatias/tratamento farmacológico , Peptídeos/farmacologia , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Animais , Arteriosclerose/patologia , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose/tratamento farmacológico , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Potássio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases da Família src/metabolismo
17.
J Ethnopharmacol ; 231: 302-310, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30342194

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ribes diacanthum Pall (RDP), a folk medicine, has been widely used in Mongolia to treat urinary system diseases. AIM OF THE STUDY: To investigate the effectiveness of RDP on unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis and the underlying mechanisms. MATERIALS AND METHODS: A total of 60 mice were randomly divided into six groups: sham group, sham plus RDP (40 mg/kg) group, UUO model group, and UUO model plus RDP (10, 20 or 40 mg/kg) groups. After surgery, aqueous extract of RDP were administrated intragastrically (i.g) daily for a week and ipsilateral kidneys were collected seven days after surgery. Levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were detected to reflect the kidney injury. Hematoxylin & eosin and Masson's trichrome staining were used to evaluate the kidney morphological changes and fibrosis, respectively. ELISA was used to examine the levels of pro-inflammatory cytokines. Immunohistochemistry, western blot and PCR were used to examine the expression levels of key proteins involved in transforming growth factor (TGF-ß)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. RESULTS: RDP treatment attenuates the level of BUN and kidney fibrosis in UUO mice, decreases the expressions of interleukin-6, tumor necrosis factor-α, Interleukin-1α, TGF-ß1, monocyte chemotactic protein-1, α-smooth muscle actin, collagen I, fibronectin, and vimentin, while increases the expressions of E-cadherin and hepatocyte growth factor. Moreover, RDP administration significantly decreases the levels of p-Smad2/3, p-ERK1/2, p-p38 and p-JNK, while increases the expression level of Smad7 in UUO models. CONCLUSION: These data demonstrate that RDP ameliorates renal fibrosis through TGF-ß/Smad and MAPK pathways in a UUO mouse model.


Assuntos
Citocinas/metabolismo , Nefropatias/metabolismo , Extratos Vegetais/farmacologia , Ribes , Obstrução Ureteral/metabolismo , Animais , Linhagem Celular , Citocinas/genética , Fibrose , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Masculino , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fitoterapia , Componentes Aéreos da Planta , Extratos Vegetais/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico
18.
Gene ; 688: 34-43, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30472381

RESUMO

BACKGROUND: Renal fibrosis promotes the progression of chronic renal disease to end-stage renal disease. Microvascular damage and loss play an important role in renal fibrosis. Intermedin (IMD) is expressed mainly in the heart and kidney. IMD has been shown to increase renal blood flow and reduce the loss of glomerular and surrounding renal tubules, but its role in mediating microvascular damage in renal fibrosis remains to be elucidated. Here, we investigated the effects of IMD on microvascular damage in a renal fibrosis model. METHODS: We created a rat model of unilateral ureteral obstruction (UUO) to clarify the effect of microvascular damage on renal fibrosis and the effect of intermedin on reversing renal vascular injury and promoting angiogenesis. Rats were divided randomly into three groups: sham, UUO, and UUO + IMD. The sham group underwent free ureteral ligation but not occlusion. Rats in the latter two groups underwent UUO, and rats in the IMD group were additionally administered intermedin (100 ng/kg/h) daily. On the 7th, 14th, 21st, and 28th days after surgery, abdominal aortic blood and the obstructed kidneys were harvested from the rats (n = 6) for analysis. RESULTS: IMD was found to protect against renal vascular injury and to increase microvessel density. Molecularly, IMD upregulated vascular endothelial growth factor-vascular endothelial growth factor receptor (VEGF-VEGFR2) pathway activity. The VEGF-VEGFR2 pathway might be the underlying mechanism mediating the protective activities of IMD in promoting angiogenesis, delaying renal fibrosis, and improving renal function. CONCLUSION: IMD could be a potential candidate treatment for renal fibrosis.


Assuntos
Adrenomedulina/metabolismo , Fibrose/metabolismo , Nefropatias/metabolismo , Neovascularização Patológica/metabolismo , Neuropeptídeos/metabolismo , Animais , Modelos Animais de Doenças , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Ratos , Ratos Wistar , Regulação para Cima/fisiologia , Obstrução Ureteral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Int J Med Sci ; 15(13): 1433-1442, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443162

RESUMO

Renal tubule cell apoptosis plays a pivotal role in the progression of chronic renal diseases. The previous study indicates that Sirolimus is effective on unilateral ureteral obstruction (UUO)-induced renal fibrosis. However, the role of Sirolimus in renal tubular apoptosis induced by UUO has not yet been addressed. The aim of this study was to determine the role of Sirolimus in renal tubular apoptosis induced by UUO. Male Sprague-Dawley rats were divided into three groups, sham-operated rats, and after which unilateral ureteral obstruction (UUO) was performed: non-treated and sirolimus-treated (1mg/kg). After 4, 7 and 14 d, animals were sacrificed and blood, kidney tissue samples were collected for analyses. Histologic changes and interstitial collagen were determined microscopically following HE and Masson's trichrome staining. The expression of PCNA was investigated using immunohistochemistry and the expression of Bcl-2, Bax, caspase-9, and caspase-3 were investigated using Western blot in each group. Tubular apoptotic cell deaths were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Sirolimus administration resulted in a significant reduction in tubulointerstitial fibrosis scores. After UUO, there was an increase in tubular and interstitial apoptosis in untreated controls as compared to Sirolimus treatment rats (P<0.05). In addition, the expression of PCNA, Bcl-2, Bax, caspase-9, and caspase-3 in obstructed kidney was characterized by immunohistochemistry and Western blot analyses demonstrating that sirolimus treatment significantly reduced PCNA, Bax, caspase-9 and cleaved caspase-3 expression compared to those observed in controls (P<0.05), whereas, Bcl-2 in the obstructed kidney were decreased in untreated controls compared to Sirolimus treatment rats subjected to the same time course of obstruction (P<0.05). We demonstrated a marked renoprotective effect of sirolimus by inhibition of UUO-induced renal tubular apoptosis in vivo.


Assuntos
Sirolimo/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos
20.
Clin Sci (Lond) ; 132(23): 2519-2545, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30442812

RESUMO

Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.


Assuntos
Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Hidronefrose/prevenção & controle , Rim/cirurgia , Regeneração , Obstrução Ureteral/cirurgia , Animais , Animais Recém-Nascidos , Rastreamento de Células/métodos , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hidronefrose/genética , Hidronefrose/metabolismo , Hidronefrose/patologia , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Camundongos Transgênicos , Neovascularização Fisiológica , Estresse Oxidativo , Fenótipo , Circulação Renal , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
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