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1.
Int Braz J Urol ; 46(2): 234-241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32022512

RESUMO

PURPOSE: Preoperative computed tomography or magnetic resonance (MR) imaging are commonly used for radiological evaluation of renal cell carcinoma (RCC) before radical nephrectomy or nephron sparing surgery(NSS). This study aimed to assess the role of MRI for predicting postoperative renal function by preoperative estimation of renal parenchymal volume and correlation with glomerular fi ltration rate (GFR). MATERIALS AND METHODS: A prospective observational study was conducted from February 2015 to October 2016 at a tertiary care hospital in northern India. MR imaging was done on 3 Tesla MR scanner (Signa Hdxt General Electrics, Milwaukee, USA). MR volumetry was used to estimate the renal parenchymal volume. GFR was measured in all patients using Tc99m Diethyl-triamine-penta-acetic acid using Russell's algorithm. Such measurement was done preoperatively, and postoperatively 3 months after surgery. RESULTS: 30 patients with suspected RCC underwent NSS (n=10) and radical nephrectomy (n=20). Median tumour volume was 175.7cc (range: 4.8 to 631.8cc). The median volume of the residual parenchyma on the affected side was 84.25±41.97cc while that on the unaffected side was 112.25±26.35cc. There was good correlation among the unaffected kidney volume and postoperative GFR for the radical nephrectomy group (r=0.83) as well as unaffected kidney volume, total residual kidney volume and residual volume of affected kidney with postoperative GFR for the NSS group (r=0.71, r=0.73, r=0.79 respectively; P<0.05). CONCLUSION: Preoperative residual parenchymal volume on MR renal volumetry correlates well with postoperative GFR in patients with RCC undergoing radical nephrectomy or NSS.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/cirurgia , Nefrectomia/métodos , Néfrons/cirurgia , Adulto , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Estudos Prospectivos
3.
Am J Physiol Renal Physiol ; 318(3): F628-F638, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904289

RESUMO

Excessive compensatory nephron hypertrophy (CNH) has been implicated in setting the stage for progressive nephron damage. Lack of a class III phosphatidylinositol 3-kinase (Pik3c3) inhibitor suitable for using in animals and lack of a Pik3c3-deficient animal model preclude the possibility of conclusively defining a role for Pik3c3 in CNH in previous studies. Here, we report that insertion of an Frt-flanked PGK-Neo cassette into intron 19 of the mouse Pik3c3 gene resulted in a hypomorphic allele. This allowed us to create a unique mouse model and provide the first definitive genetic evidence demonstrating whether Pik3c3 is essential for the regulation of CNH. Our results indicate that homozygous Pik3c3 hypomorphic (Pik3c3Hypo/Hypo) mice express significantly low levels of Pik3c3 than heterozygous Pik3c3 hypomorphic (Pik3c3Hypo/WT) littermates, which already express a lower level of Pik3c3 than wild-type (Pik3c3WT/WT) littermates. Interestingly, after unilateral nephrectomy (UNX), Pik3c3Hypo/Hypo mice develop a significantly lower degree of CNH than Pik3c3WT/WT mice and Pik3c3Hypo/WT mice, as revealed by measurement of kidney weight, kidney-to-body weight ratio, renal protein-to-DNA ratio, and morphometric analysis of proximal tubular and glomerular size. Mechanistically, UNX-induced mammalian target of rapamycin complex 1 (mTORC1) signaling to phosphorylation of ribosomal protein S6 (rpS6) in the remaining kidney was markedly inhibited in Pik3c3 hypomorphic mice. In conclusion, the present study reports a Pik3c3 hypomorphic mouse model and provides the first definitive evidence that Pik3c3 controls the degree of compensatory nephron hypertrophy. In addition, our signaling data provide the first definitive in vivo proof that Pik3c3 functions upstream of the mTORC1-S6 kinase 1-rpS6 pathway in the regulation of compensatory nephron hypertrophy.


Assuntos
Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Néfrons/patologia , Animais , Classe III de Fosfatidilinositol 3-Quinases/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipertrofia , Íntrons/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Mutagênese Insercional , Nefrectomia , Néfrons/metabolismo , Transdução de Sinais/fisiologia
4.
Am J Physiol Renal Physiol ; 318(1): F183-F192, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760771

RESUMO

Angiotensin II exacerbates oxidative stress in part by increasing superoxide (O2-) production by many renal tissues. However, whether it does so in proximal tubules and the source of O2- in this segment are unknown. Dietary fructose enhances the stimulatory effect of angiotensin II on proximal tubule Na+ reabsorption, but whether this is true for oxidative stress is unknown. We hypothesized that angiotensin II causes proximal nephron oxidative stress in part by stimulating NADPH oxidase (NOX)4-dependent O2- production and decreasing the amount of the antioxidant glutathione, and this is exacerbated by dietary fructose. We measured basal and angiotensin II-stimulated O2- production with and without inhibitors, NOX1 and NOX4 expression, and total and reduced glutathione (GSH) in proximal tubules from rats drinking either tap water (control) or 20% fructose. Angiotensin II (10 nM) increased O2- production by 113 ± 42 relative light units·mg protein-1·s-1 in controls and 401 ± 74 relative light units·mg protein-1·s-1 with 20% fructose (n = 11 for each group, P < 0.05 vs. control). Apocynin and the Nox1/4 inhibitor GKT136901 prevented angiotensin II-induced increases in both groups. NOX4 expression was not different between groups. NOX1 expression was undetectable. Angiotensin II decreased GSH by 1.8 ± 0.8 nmol/mg protein in controls and by 4.2 ± 0.9 nmol/mg protein with 20% fructose (n = 18 for each group, P < 0.047 vs. control). We conclude that 1) angiotensin II causes oxidative stress in proximal tubules by increasing O2- production by NOX4 and decreasing GSH and 2) dietary fructose enhances the ability of angiotensin II to stimulate O2- and diminish GSH, thereby exacerbating oxidative stress in this segment.


Assuntos
Angiotensina II/farmacologia , Glutationa/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Superóxidos/metabolismo , Acetofenonas/farmacologia , Animais , Antioxidantes/farmacologia , Açúcares da Dieta , Frutose , Túbulos Renais Proximais/metabolismo , Masculino , NADPH Oxidases/metabolismo , Néfrons/efeitos dos fármacos , Néfrons/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirazóis/farmacologia , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley
8.
Nat Rev Nephrol ; 16(2): 77-98, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31554933

RESUMO

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.


Assuntos
Lesão Renal Aguda/metabolismo , Proteínas Reguladoras do Ferro/metabolismo , Ferro/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Eritropoese , Eritropoetina/metabolismo , Homeostase , Humanos , Inflamação/metabolismo , Túbulos Renais Distais/metabolismo , Túbulos Renais Proximais/metabolismo , Mitocôndrias/metabolismo , Néfrons/metabolismo , Estresse Oxidativo
9.
Nature ; 577(7788): 121-126, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31853060

RESUMO

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.


Assuntos
Linhagem da Célula , Cromatina/genética , Proteínas de Ligação a DNA/metabolismo , Mutação com Ganho de Função , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Camundongos , Néfrons/metabolismo , Néfrons/patologia , Fatores de Transcrição/química , Fatores de Transcrição/genética
10.
Morphologie ; 103(343): 161-168, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31722814

RESUMO

We give an overview of mathematical models of renal physiology and anatomy with the clinician in mind. Beyond the past focus on issues of local transport mechanisms along the nephron and the urine concentrating mechanism, recent models have brought insight into difficult problems such as renal ischemia (oxygen and CO2 diffusion in the medulla) or calcium and potassium homeostasis. They have also provided revealing 3D reconstructions of the full trajectories of families of nephrons and collecting ducts through cortex and medulla. The recent appearance of sophisticated whole-kidney models representing nephrons and their associated renal vasculature promises more realistic simulation of renal pathologies and pharmacological treatments in the foreseeable future.


Assuntos
Imageamento Tridimensional , Modelos Biológicos , Néfrons/fisiologia , Animais , Taxa de Filtração Glomerular/fisiologia , Humanos , Modelos Animais , Néfrons/anatomia & histologia , Néfrons/diagnóstico por imagem
11.
Dev Cell ; 51(3): 399-413.e7, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31689386

RESUMO

Chronic kidney disease affects 10% of the population with notable differences in ethnic and sex-related susceptibility to kidney injury and disease. Kidney dysfunction leads to significant morbidity and mortality and chronic disease in other organ systems. A mouse-organ-centered understanding underlies rapid progress in human disease modeling and cellular approaches to repair damaged systems. To enhance an understanding of the mammalian kidney, we combined anatomy-guided single-cell RNA sequencing of the adult male and female mouse kidney with in situ expression studies and cell lineage tracing. These studies reveal cell diversity and marked sex differences, distinct organization and cell composition of nephrons dependent on the time of nephron specification, and lineage convergence, in which contiguous functionally related cell types are specified from nephron and collecting system progenitor populations. A searchable database, Kidney Cell Explorer (https://cello.shinyapps.io/kidneycellexplorer/), enables gene-cell relationships to be viewed in the anatomical framework of the kidney.


Assuntos
Linhagem da Célula , Rim/citologia , Caracteres Sexuais , Análise de Célula Única , Animais , Células Epiteliais/citologia , Feminino , Rim/anatomia & histologia , Masculino , Camundongos , Néfrons/citologia , Fatores de Tempo
12.
Am J Physiol Renal Physiol ; 317(6): F1462-F1474, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31566436

RESUMO

The goal of the present study was to investigate the functional implications of sexual dimorphism in the pattern of transporters along the rodent nephron as reported by Veiras et al. (J Am Soc Nephrol 28: 3504-3517, 2017). To do so, we developed sex-specific computational models of water and solute transport along the superficial nephrons from male and female rat kidneys. The models account for the sex differences in the abundance of apical and basolateral transporters, single nephron glomerular filtration rate, and tubular dimensions. Model simulations predict that ~70% and 60% of filtered Na+ is reabsorbed by the proximal tubule of male and female rat kidneys, respectively. The lower fractional Na+ reabsorption in female kidneys is due primarily to their smaller transport area, lower Na+/H+ exchanger activity, and lower claudin-2 abundance, culminating in significantly larger fractional delivery of water and Na+ to the downstream nephron segments in female kidneys. Conversely, the female distal nephron exhibits a higher abundance of key Na+ transporters, including Na+-K+-Cl- cotransporters, Na+-Cl- cotransporters, and epithelial Na+ channels. The higher abundance of transporters accounts for the enhanced water and Na+ transport along the female, relative to male, distal nephron, resulting in similar urine excretion between the sexes. Consequently, in response to a saline load, the Na+ load delivered distally is greater in female rats than male rats, overwhelming transport capacity and resulting in higher natriuresis in female rats.


Assuntos
Proteínas de Transporte/metabolismo , Néfrons/metabolismo , Animais , Claudinas/metabolismo , Feminino , Taxa de Filtração Glomerular , Túbulos Renais/metabolismo , Masculino , Modelos Biológicos , Ratos , Caracteres Sexuais , Sódio/metabolismo , Sódio/urina , Canais de Sódio/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Água/metabolismo
13.
Am J Physiol Renal Physiol ; 317(5): F1398-F1403, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588797

RESUMO

Our current knowledge of the properties of renal ion channels responsible for electrolytes and cell energy homeostasis mainly relies on rodent studies. However, it has not been established yet to what extent their characteristics can be generalized to those of humans. The present study was designed to develop a standardized protocol for the isolation of well-preserved glomeruli and renal tubules from rodent and human kidneys and to assess the functional suitability of the obtained materials for physiological studies. Separation of nephron segments from human and rodent kidneys was achieved using a novel vibrodissociation technique. The integrity of isolated renal tubules and glomeruli was probed via electrophysiological analysis and fluorescence microscopy, and the purity of the collected fractions was confirmed using quantitative RT-PCR with gene markers for specific cell types. The developed approach allows rapid isolation of well-preserved renal tubules and glomeruli from human and rodent kidneys amenable for electrophysiological, Ca2+ imaging, and omics studies. Analysis of the basic electrophysiological parameters of major K+ and Na+ channels expressed in human cortical collecting ducts revealed that they exhibited similar biophysical properties as previously reported in rodent studies. Using vibrodissociation for nephron segment isolation has several advantages over existing techniques: it is less labor intensive, requires little to no enzymatic treatment, and produces large quantities of well-preserved experimental material in pure fractions. Applying this method for the separation of nephron segments from human and rodent kidneys may be a powerful tool for the indepth assessment of kidney function in health and disease.


Assuntos
Técnicas de Preparação Histocitológica/métodos , Néfrons , Animais , Cálcio/metabolismo , Humanos , Camundongos , Ratos , Ratos Endogâmicos Dahl , Vibração
14.
J Surg Oncol ; 120(7): 1220-1226, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31602673

RESUMO

BACKGROUND AND OBJECTIVES: Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern. METHODS: This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018. RESULTS: A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m2 BSA n = 36; 175 mg/m2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%). CONCLUSIONS: Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Hipertermia Induzida/efeitos adversos , Mesotelioma/terapia , Néfrons/efeitos dos fármacos , Neoplasias Pleurais/terapia , Substâncias Protetoras/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Amifostina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Creatinina/sangue , Citoproteção , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Cuidados Pós-Operatórios , Prognóstico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Tiossulfatos/administração & dosagem , Cavidade Torácica/cirurgia
16.
Am J Physiol Renal Physiol ; 317(6): F1656-F1668, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657247

RESUMO

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg-1·min-1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl- cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg-1·min-1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl- cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.


Assuntos
Angiotensina II/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Néfrons/metabolismo , Sódio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Creatinina/metabolismo , Canais Epiteliais de Sódio , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Lítio/urina , Masculino , Natriurese/efeitos dos fármacos , Potássio/metabolismo , Ratos , Sódio/urina , Trocador 3 de Sódio-Hidrogênio/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/metabolismo
17.
Niger J Clin Pract ; 22(10): 1396-1402, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31607729

RESUMO

Background: Nephron-sparing surgery (NSS) is currently the recommended treatment modality for selected renal tumors. The prognostic significance of positive surgical margin (PSM) and surgical margin width (SMW) after NSS is controversial. Aim: To evaluate the effect of PSM and SMW on cancer-specific survival (CSS) in patients who underwent NSS. Materials and Methods: The pathological samples of 142 patients who underwent NSS were reviewed. Patients were divided into two groups with PSM and negative surgical margin (NSM), and after that those with PSM were divided into two groups according to SMW as those with 0.1-2 mm and those >2 mm. CSS was calculated using Kaplan-Meier method. Cox regression analysis was used to adjust the clinicopathologic variables. A P value < 0.05 was considered statistically significant. Results: Local recurrence rate and distant metastasis rate were higher in patients with PSMs than those with NSMs (P = 0.018 and P = 0.039, respectively). However, there was no significant difference between the two groups in terms of CSS. In the group with SMW 0.1-2 mm, the tumor diameter was longer (P = 0.018), enucleation number was higher (P = 0.026), and local recurrence was higher (P = 0.034) than the group with SMW > 2 mm. There was no significant difference between the two groups in terms of CSS. Conclusion: In patients who underwent NSS, PSMs and SMWs have a negative effect on local recurrence but have no significant effect on CSS.


Assuntos
Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Margens de Excisão , Recidiva Local de Neoplasia/mortalidade , Nefrectomia/mortalidade , Néfrons/cirurgia , Tratamentos com Preservação do Órgão/mortalidade , Tratamentos com Preservação do Órgão/métodos , Idoso , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Néfrons/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
18.
Commun Biol ; 2: 326, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508501

RESUMO

The kidney's inherent complexity has made identifying cell-specific pathways challenging, particularly when temporally associating them with the dynamic pathophysiology of acute kidney injury (AKI). Here, we combine renal cell-specific luciferase reporter mice using a chemoselective luciferin to guide the acquisition of cell-specific transcriptional changes in C57BL/6 background mice. Hydrogen peroxide generation, a common mechanism of tissue damage, was tracked using a peroxy-caged-luciferin to identify optimum time points for immunoprecipitation of labeled ribosomes for RNA-sequencing. Together, these tools revealed a profound impact of AKI on mitochondrial pathways in the collecting duct. In fact, targeting the mitochondria with an antioxidant, ameliorated not only hydrogen peroxide generation, but also significantly reduced oxidative stress and the expression of the AKI biomarker, LCN2. This integrative approach of coupling physiological imaging with transcriptomics and drug testing revealed how the collecting duct responds to AKI and opens new venues for cell-specific predictive monitoring and treatment.


Assuntos
Lesão Renal Aguda/genética , Imageamento Tridimensional , Isquemia/genética , Isquemia/patologia , Transcriptoma/genética , Lesão Renal Aguda/complicações , Lesão Renal Aguda/patologia , Animais , Antioxidantes/metabolismo , Túbulos Renais Coletores/lesões , Túbulos Renais Coletores/patologia , Camundongos Endogâmicos C57BL , Néfrons/metabolismo , Néfrons/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
19.
Eur J Histochem ; 63(3)2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31544449

RESUMO

Nephron progenitors (NPs) and nephrogenesis have been extensively studied in mice and humans and have provided insights into the mechanisms of renal development, disease and possibility of NP-based therapies. However, molecular features of NPs and their derivatives in the canine fetal kidney (CFK) remain unknown. This study was focused to characterize the expression of potential markers of canine NPs and their derivatives by immuno-fluorescence and western blot analysis. Transcription factors (TFs) SIX1 and SIX2, well-characterized human NP markers, were expressed in NPs surrounding the ureteric bud in the CFK. Canine NPs also expressed ITGA8 and NCAM1, surface markers previously used to isolate NPs from the mouse and human fetal kidneys. TF, PAX2 was detected in the ureteric bud, NPs and their derivative structures such as renal vesicle and S-shaped body. This study highlights the similarities in dog, mouse and human renal development and characterizes markers to identify canine NPs and their derivatives. These results will facilitate the isolation of canine NPs and their functional characterization to develop NP-based therapies for canine renal diseases.


Assuntos
Células Epiteliais/metabolismo , Néfrons/metabolismo , Fatores de Transcrição/metabolismo , Animais , Biomarcadores/metabolismo , Western Blotting , Cães/embriologia , Células Epiteliais/citologia , Feminino , Imunofluorescência , Néfrons/citologia , Gravidez
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