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1.
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
2.
J Am Soc Nephrol ; 31(2): 415-423, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974271

RESUMO

BACKGROUND: Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. METHODS: Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. RESULTS: The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. CONCLUSIONS: Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft's "intrinsic quality" at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.


Assuntos
Rejeição de Enxerto , Transplante de Rim/efeitos adversos , Rim/patologia , Doadores Vivos , Adulto , Idoso , Biópsia , Feminino , Humanos , Rim/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Néfrons/patologia , Tomografia Computadorizada por Raios X
3.
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
5.
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
6.
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
7.
Curr Opin Nephrol Hypertens ; 28(6): 545-551, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433316

RESUMO

PURPOSE OF REVIEW: Many studies have suggested low nephron endowment at birth contributes to the risk of developing hypertension and chronic kidney disease (CKD) later in life. Loss of nephrons with age and disease is largely a subclinical process. New technologies are needed to count nephrons as glomerular filtration rate (GFR) is a poor surrogate for nephron number. RECENT FINDINGS: Cortical volume, glomerular density, and percent globally sclerotic glomeruli are imperfect surrogates for nephron number. The disector-fractionator method is the most accurate method to count nephrons but is limited to autopsy settings. Glomerular density combined with kidney imaging and ultrafiltration coefficient-based methods require a kidney biopsy, and have been applied in living humans (kidney donors). Low nephron number predicts a higher postdonation urine albumin. Contrast-enhanced MRI has detected glomeruli without a biopsy, but so far, not in living humans. SUMMARY: Currently, there is no accurate and well tolerated method for determining nephron number in living humans. A clinically useful method may allow GFR to be replaced by its more relevant determinants: nephron number and single nephron GFR. This could revolutionize nephrology by separating the measurement of chronic disease (nephron loss) from more reversible hemodynamic effects (nephron hyperfiltration/hypofiltration).


Assuntos
Néfrons/patologia , Biópsia , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Glomérulos Renais/patologia , Imagem por Ressonância Magnética , Néfrons/diagnóstico por imagem
8.
Stem Cell Reports ; 13(2): 322-337, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31378669

RESUMO

Kidney formation is regulated by the balance between maintenance and differentiation of nephron progenitor cells (NPCs). Now that directed differentiation of NPCs from human induced pluripotent stem cells (iPSCs) can be achieved, maintenance and propagation of NPCs in vitro should be beneficial for regenerative medicine. Although WNT and FGF signals were previously shown to be essential for NPC propagation, the requirement for BMP/TGFß signaling remains controversial. Here we reveal that activin has superior effects to BMP7 on maintenance efficiency of human iPSC-derived NPCs. Activin expanded ITGA8+/PDGFRA-/SIX2-GFP+ NPCs by 5-fold per week at 80%-90% efficiency, and the propagated cells possessed robust capacity for nephron formation both in vitro and in vivo. The expanded cells also maintained their nephron-forming potential after freezing. Furthermore, the protocol was applicable to multiple non-GFP-tagged iPSC lines. Thus, our activin-based protocol will be applicable to a variety of research fields including disease modeling and drug screening.


Assuntos
Ativinas/farmacologia , Proteína Morfogenética Óssea 7/farmacologia , Proliferação de Células/efeitos dos fármacos , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Diferenciação Celular , Reprogramação Celular , Edição de Genes , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Camundongos , Néfrons/citologia , Néfrons/metabolismo , Néfrons/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Podócitos/metabolismo , Podócitos/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Transplante de Células-Tronco , Células-Tronco/citologia , Células-Tronco/metabolismo
9.
Am J Physiol Renal Physiol ; 317(4): F865-F873, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339774

RESUMO

The development of chronic kidney disease (CKD) is associated with the loss of functional nephrons. However, there are no methods to directly measure nephron number in living subjects. Thus, there are no methods to track the early stages of progressive CKD before changes in total renal function. In this work, we used cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) to enable measurements of glomerular number (Nglom) and apparent glomerular volume (aVglom) in vivo in healthy wild-type (WT) mice (n = 4) and mice with oligosyndactylism (Os/+; n = 4), a model of congenital renal hypoplasia leading to nephron reduction. We validated in vivo measurements of Nglom and aVglom by high-resolution ex vivo MRI. CFE-MRI measured a mean Nglom of 12,220 ± 2,028 and 6,848 ± 1,676 (means ± SD) for WT and Os/+ mouse kidneys in vivo, respectively. Nglom measured in all mice in vivo using CFE-MRI varied by an average 15% from Nglom measured ex vivo in the same kidney (α = 0.05, P = 0.67). To confirm that CFE-MRI can also be used to track nephron endowment longitudinally, a WT mouse was imaged three times by CFE-MRI over 2 wk. Values of Nglom measured in vivo in the same kidney varied within ~3%. Values of aVglom calculated from CFE-MRI in vivo were significantly different (~15% on average, P < 0.01) from those measured ex vivo, warranting further investigation. This is the first report of direct measurements of Nglom and aVglom in healthy and diseased mice in vivo.


Assuntos
Glomérulos Renais/patologia , Sindactilia/patologia , Animais , Progressão da Doença , Processamento de Imagem Assistida por Computador , Nefropatias/congênito , Nefropatias/diagnóstico por imagem , Nefropatias/patologia , Glomérulos Renais/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Néfrons/patologia , Razão Sinal-Ruído , Sindactilia/diagnóstico por imagem
10.
Physiol Rep ; 7(9): e14044, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31087539

RESUMO

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD+ -dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age-related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1Y/Y ) mice had lower GFRs and fewer glomeruli than their wild-type (Sirt1+/+ ) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.


Assuntos
Envelhecimento/fisiologia , Taxa de Filtração Glomerular/fisiologia , Glomérulos Renais/patologia , Sirtuína 1/fisiologia , Envelhecimento/patologia , Animais , Peso Corporal/fisiologia , Modelos Animais de Doenças , Histona Desacetilases/metabolismo , Rim/patologia , Masculino , Camundongos Mutantes , Néfrons/patologia , Tamanho do Órgão/fisiologia , Mutação Puntual , Sirtuína 1/deficiência , Sirtuína 1/genética
11.
J Urol ; 202(5): 890-898, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31145034

RESUMO

PURPOSE: We examined interdisciplinary variability using 2 established preoperative nephrometry scores to predict conversion to nephrectomy in patients with a renal mass who were scheduled for partial nephrectomy. MATERIALS AND METHODS: A total of 229 consecutive candidates for partial nephrectomy were included in this study at a single institution between January 2013 and May 2017. Patient, tumor and treatment characteristics were assessed. The PADUA (preoperative aspects and dimensions used for an anatomical) score and the R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines) score were independently calculated by board certified radiologists and urological residents using computerized tomography or magnetic resonance imaging. Statistical analyses were done with the κ statistic, ROC curves, and univariable and multivariable binary logistic regression analyses. RESULTS: Partial nephrectomy was performed in 198 of the 229 cases (86.5%) while 31 (13.5%) were converted to nephrectomy. The prevalent tumor stage was pT1a, noted in 94 of the 229 cases (41.1%), and the predominant histological entity was clear cell carcinoma, found in 128 (55.9%). Radiologist and urologist interdisciplinary comparison of the PADUA and R.E.N.A.L. scores revealed a κ of 0.40 and 0.56, respectively. ROC curve analyses demonstrated a higher AUC predicting conversion to nephrectomy using the PADUA score by the urologist and the radiologist (0.79 and 0.782) compared to that of the R.E.N.A.L. score (0.731 and 0.766, respectively). Using a cutoff of 10 or greater the PADUA score determined by the urologist had 81% sensitivity and 71% specificity, and it was independently associated with conversion to nephrectomy (OR 10.98, p<0.001). CONCLUSIONS: Our results indicate higher prediction of conversion to nephrectomy when using the PADUA score compared to the R.E.N.A.L. score. Calculation of the PADUA and the R.E.N.A.L. score by physicians without specialized radiological training is feasible and might achieve comparable results to predict conversion to nephrectomy compared to the gold standard provided by board certified radiologists. This information is helpful if nephrometry scores are not regularly included in the radiology report.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Laparoscopia/métodos , Estadiamento de Neoplasias , Nefrectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico , Feminino , Taxa de Filtração Glomerular , Humanos , Neoplasias Renais/diagnóstico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Néfrons/patologia , Curva ROC , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
12.
Semin Nephrol ; 39(2): 190-201, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827341

RESUMO

Drug-induced kidney toxicity is a significant contributor to acute kidney injury. Nephrotoxic drugs need to be identified during nonclinical testing to highlight potential risk translatable to the intended patient population. When nonclinical kidney toxicity signals arise, scientists and physicians affiliated with clinical trials need to be familiar with commonly encountered drug-induced perturbations in the kidney, terminology, and how these changes relate to clinical risk. Mechanistic and translational toxicologic studies beyond routine histopathology and clinical pathology approaches may be needed to elucidate the pathogenesis and human relevance to inform clinical risk assessment. Investigational studies may help elucidate specific sites of injury within the nephron, the presence of reactive metabolites, mechanisms of membrane transport or tissue distribution, potential drug-drug interactions, or the ability to recover function after drug withdrawal. Cutting-edge techniques such as in vitro alternative platforms, humanized animal models, translational imaging/microscopy or circulating/secretory biomarkers, omics platforms at the interface of genes, proteins, metabolites, or advanced molecular and biochemical approaches provide toxicologists and pathologists with a wide variety of potential experimental modalities to investigate mechanisms of kidney toxicity.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Néfrons/patologia , Lesão Renal Aguda/diagnóstico por imagem , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Animais Geneticamente Modificados , Linhagem Celular , Cães , Desenvolvimento de Medicamentos , Técnicas de Inativação de Genes , Humanos , Técnicas In Vitro , Rim/diagnóstico por imagem , Rim/metabolismo , Rim/patologia , Camundongos , Microvilosidades , Modelos Animais , Néfrons/diagnóstico por imagem , Néfrons/metabolismo , Cultura Primária de Células , Ratos , Peixe-Zebra
13.
Kidney Int ; 95(3): 624-635, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30784661

RESUMO

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.


Assuntos
Envelhecimento/genética , Néfrons/patologia , Insuficiência Renal Crônica/genética , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Biologia Computacional , Metilação de DNA/genética , Epigenômica , Feminino , Perfilação da Expressão Gênica , Variação Genética , Taxa de Filtração Glomerular/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lactoferrina/genética , Masculino , Pessoa de Meia-Idade , Muramidase/genética , Néfrons/fisiopatologia , Proteínas Nucleares/genética , RNA-Seq , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia
14.
J Dev Orig Health Dis ; 10(2): 154-163, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30274564

RESUMO

Maternal insufficiency during fetal development can have long-lasting effects on the offspring, most notably on nephron endowment. In polycystic kidney disease (PKD), variability in severity of disease is observed and maternal environment may be a modifying factor. In this study, we first established that in a rodent model of PKD, the Lewis polycystic kidney (LPK) rat's nephron numbers are 25% lower compared with wildtype animals. We then investigated the effects of prenatal and postnatal maternal environment on phenotype and nephron number. LPK pups born from and raised by homozygous LPK dams (control) were compared with LPK pups cross-fostered onto heterozygous LPK dams to improve postnatal environment; with LPK pups born from and raised by heterozygous LPK dams to improve both prenatal and postnatal environment and with LPK pups born from and raised by Wistar Kyoto-LPK heterozygous dams to improve both prenatal and postnatal environment on a different genetic background. Improvement in both prenatal and postnatal environment improved postnatal growth, renal function and reduced blood pressure, most notably in animals with different genetic background. Animals with improved postnatal environment only showed improved growth and blood pressure, but to a lesser extent. All intervention groups showed increased nephron number compared with control LPK. In summary, prenatal and postnatal environment had significant effect in delaying progression and reducing severity of PKD, including nephron endowment.


Assuntos
Desenvolvimento Fetal/genética , Hipertensão/fisiopatologia , Quinases Relacionadas a NIMA/genética , Néfrons/fisiopatologia , Doenças Renais Policísticas/genética , Animais , Animais Recém-Nascidos/fisiologia , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Feminino , Heterozigoto , Homozigoto , Hipertensão/etiologia , Lactação/fisiologia , Masculino , Camundongos Transgênicos , Mutação , Néfrons/crescimento & desenvolvimento , Néfrons/patologia , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/fisiopatologia , Gravidez , Ratos , Ratos Endogâmicos Lew , Índice de Gravidade de Doença
15.
Clin Genitourin Cancer ; 17(1): e26-e31, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30266249

RESUMO

BACKGROUND: The role of positive surgical margins (PSMs) on the recurrence of renal cell carcinoma (RCC) after partial nephrectomy (PN) is debated, and available evidence lacks long-term data. The aim of this study was to evaluate the predictive role of PSMs on progression-free survival (PFS) in a large cohort followed for at least 5 years. METHODS: This study was a retrospective analysis of a prospectively compiled single-institution database collecting complete information on more than 2700 patients who had undergone surgery for renal tumor. The data of all the patients submitted to PN for RCC and with least 5 years follow-up were extracted. Surgical specimens were examined at the time of surgery only by 2 expert uro-pathologists. A PSM was defined as the presence of cancer cells at the inked surface of the specimen. The role of PSMs on survival was estimated by Cox regression models adjusted for influent covariates. RESULTS: A total of 459 patients fulfilled the inclusion criteria and were evaluated. PSMs were observed in 27 (5.9%) cases. No differences in preoperative and pathologic data were found comparing patients with and without PSMs. At a median follow-up of 96 months (interquartile range, 74-131 months), a clinically evident relapse of RCC was diagnosed in 36 (7.8%) patients at a median interval of 36 months from PN. Among these, 6 had a PSM for an incidence of relapse of 22.2% in the PSM group, whereas 30 had negative margins, for an incidence of 6.9% (P = .013). The sites of relapse were distant organs in 18 cases, and the kidney underwent PN in 21. The patients with PSMs showed a borderline significantly higher incidence of distant metastasis (11.1% vs. 3.5%; P = .071) and a significantly higher incidence of renal relapses (14.8% vs. 3.9%; P = .029). Multivariable Cox models confirmed that the presence of PSMs was an independent predictor of PFS (odds ratio, 3.127; P = .013). CONCLUSIONS: PSMs are an independent predictor of PFS in patients who underwent PN for RCC, owing to a higher incidence of distant and local relapses. Surveillance in presence of PSMs should be intensified and extended for a long time.


Assuntos
Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Margens de Excisão , Recidiva Local de Neoplasia/mortalidade , Nefrectomia/mortalidade , Néfrons/cirurgia , Tratamentos com Preservação do Órgão/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Néfrons/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
16.
Anticancer Res ; 38(12): 6663-6667, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30504374

RESUMO

BACKGROUND/AIM: The association of Wilms' tumor (WT), papillary renal cell tumor (PRCT) and mucinous tubular and spindle cell carcinoma (MTSCC) with embryonal rests has already been documented, but the cellular origin of metanephric adenoma (MA) is not yet known. The aim of this study was to understand their developmental evolution and find diagnostic markers. MATERIALS AND METHODS: CD57, KRT7, AMACR, SCEL, WT1 and CDH17 expression was analysed by immunohistochemistry in the four types of tumors and the associated pre-neoplastic lesions. RESULTS: Immunohistochemistry was able to differentiate WT, MA, MTSCC and PRCT. A phenotypic correlation between MA and perilobar nephrogenic rest associated with WT was identified. CONCLUSION: Perilobar nephrogenic rest and MA arise from differentiation arrested cells of the proximal domain of the S-shape body. We propose that WT1, MA, MTSCC and PRCT derive from different forms of maturation arrested embryonal rests.


Assuntos
Adenoma/diagnóstico , Adenoma/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Rim/embriologia , Néfrons/embriologia , Adenoma/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Diferenciação Celular , Diagnóstico Diferencial , Embrião de Mamíferos , Feminino , Feto/metabolismo , Feto/patologia , Humanos , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Neoplasias Renais/metabolismo , Néfrons/metabolismo , Néfrons/patologia , Gravidez , Análise Serial de Tecidos , Tumor de Wilms/diagnóstico , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia
17.
J Am Soc Nephrol ; 29(11): 2627-2640, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30301860

RESUMO

BACKGROUND: The familial hyperkalemic hypertension (FHHt) cullin 3 (CUL3) mutant does not degrade WNK kinases normally, thereby leading to thiazide-sensitive Na-Cl cotransporter (NCC) activation. CUL3 mutant (CUL3Δ9) does not bind normally to the COP9 signalosome (CSN), a deneddylase involved in regulating cullin-RING ligases. CUL3Δ9 also caused increased degradation of the CUL3-WNK substrate adaptor kelch-like 3 (KLHL3). Here, we sought to determine how defective CSN action contributes to the CUL3Δ9 phenotype. METHODS: The Pax8/LC1 mouse system was used to generate mice in which the catalytically active CSN subunit, Jab1, was deleted only along the nephron, after full development (KS-Jab1 -/-). RESULTS: Western blot analysis demonstrated that Jab1 deletion increased the abundance of neddylated CUL3. Moreover, total CUL3 expression was reduced, suggesting decreased CUL3 stability. KLHL3 was almost completely absent in KS-Jab1 -/- mice. Conversely, the protein abundances of WNK1, WNK4, and SPAK kinases were substantially higher. Activation of WNK4, SPAK, and OSR1 was indicated by higher phosphorylated protein levels and translocation of the proteins into puncta, as observed by immunofluorescence. The ratio of phosphorylated NCC to total NCC was also higher. Surprisingly, NCC protein abundance was low, likely contributing to hypokalemia and Na+ and K+ wasting. Additionally, long-term Jab1 deletion resulted in kidney damage. CONCLUSIONS: Together, the results indicate that deficient CSN binding contributes importantly to the FHHt phenotype. Although defective CUL3Δ9-faciliated WNK4 degradation likely contributes, dominant effects on KLHL3 may be a second factor that is necessary for the phenotype.


Assuntos
Complexo do Signalossomo COP9/deficiência , Complexo do Signalossomo COP9/genética , Rim/metabolismo , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/metabolismo , Animais , Complexo do Signalossomo COP9/metabolismo , Proteínas Culina/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Microscopia de Fluorescência , Mutação , Néfrons/metabolismo , Néfrons/patologia , Peptídeo Hidrolases/deficiência , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Pseudo-Hipoaldosteronismo/patologia , Transdução de Sinais
18.
Math Biosci ; 305: 77-95, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30196120

RESUMO

Determining the future state of individual patients, with regard to the susceptibility to life-threatening condition is a crucial problem in the public health. Chronic Kidney Disease (CKD) is a perilous disease, which is characterized by gradual loss of kidney function. This paper presents a set of mathematical models for CKD by applying both deterministic and stochastic approaches. Specifically, hypertension and stress are considered as the main causes of damaging and removing of nephrons thereby reducing the Glomerular Filtration Rate (GFR), which leads to irreparable damages to the kidney function and may result in renal failure, or even kidney loss. This paper analyzes the equilibria for both deterministic and stochastic models. In this regard, mathematical theorems related to stability and stochastic stability of the models are provided. The other important issue, which is discussed in the presented work, is the uncertainty problem for stochastic models. We have used simulations in MATLAB to calculate the uncertainty of the stochastic models. In addition, we have provided a framework for the future prediction of proposed models in specific cases. Finally, the models and the theoretical results are verified in application by applying them to the real clinical data.


Assuntos
Hipertensão/fisiopatologia , Rim/fisiopatologia , Modelos Biológicos , Simulação por Computador , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Hipertensão/patologia , Rim/patologia , Conceitos Matemáticos , Néfrons/patologia , Néfrons/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Processos Estocásticos , Estresse Fisiológico , Incerteza
19.
Clin. transl. oncol. (Print) ; 20(9): 1196-1201, sept. 2018. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-173705

RESUMO

Objective: To evaluate the pathological features and define the optimal surgical margins (SM) of nephron-sparing surgery (NSS) for kidney neoplasms 4-7 cm (stage pT1b) on preoperative imaging. Materials and methods: The retrospective study included 748 patients who were diagnosed stage pT1b renal tumors and underwent either radical nephrectomy (RN, n = 475) or NSS (n = 273) from January 2004 to March 2017. The tumor size, pathological subtype, Fuhrman grade, status of peritumoral pseudocapsule (PC) and tumor multifocality were recorded. The relationship between peritumoral PC and positive SM was calculated statistically by Fisher's exact probability test. Results: The mean tumor diameter was 5.4 cm (range: 4.1-7.0 cm), 65 (8.7%) cases were discovered with multifocal lesions and 686 (91.7%) were surrounded with peritumoral PC in all 748 specimens. 57 (8.3%) of 686 cases were proved with tumor infiltrated beyond PC [infiltration (+)], and the presence of PC infiltration (+) was significantly correlated with positive SM (p = 0.016). The infiltrative depth of tumor cells into renal parenchyma beyond PC was all limited in 3 mm and the proportion of ≤ 1, 1-2 and 2-3 mm was 21.1% (12/57), 59.6% (34/57) and 19.3% (11/57), respectively. Conclusions: Our report indicates a 3 mm excisional margin is acceptable to ensure negative SM when operating NSS on stage pT1b kidney neoplasms


No disponible


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Margens de Excisão , Neoplasias Renais/patologia , Tratamentos com Preservação do Órgão/métodos , Neoplasias Renais/cirurgia , Néfrons/patologia , Néfrons/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
20.
Adv Chronic Kidney Dis ; 25(4): 321-333, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30139459

RESUMO

In contrast to distal type I or classic renal tubular acidosis (RTA) that is associated with hypokalemia, hyperkalemic forms of RTA also occur usually in the setting of mild-to-moderate CKD. Two pathogenic types of hyperkalemic metabolic acidosis are frequently encountered in adults with underlying CKD. One type, which corresponds to some extent to the animal model of selective aldosterone deficiency (SAD) created experimentally by adrenalectomy and glucocorticoid replacement, is manifested in humans by low plasma and urinary aldosterone levels, reduced ammonium excretion, and preserved ability to lower urine pH below 5.5. This type of hyperkalemic RTA is also referred to as type IV RTA. It should be noted that the mere deficiency of aldosterone when glomerular filtration rate is completely normal only causes a modest decline in plasma bicarbonate which emphasizes the importance of reduced glomerular filtration rate in the development of the hyperchloremic metabolic acidosis associated with SAD. Another type of hyperkalemic RTA distinctive from SAD in which plasma aldosterone is not reduced is referred to as hyperkalemic distal renal tubular acidosis because urine pH cannot be reduced despite acidemia or after provocative tests aimed at increasing sodium-dependent distal acidification such as the administration of sodium sulfate or loop diuretics with or without concurrent mineralocorticoid administration. This type of hyperkalemic RTA (also referred to as voltage-dependent distal renal tubular acidosis) has been best described in patients with obstructive uropathy and resembles the impairment in both hydrogen ion and potassium secretion that are induced experimentally by urinary tract obstruction and when sodium transport in the cortical collecting tubule is blocked by amiloride.


Assuntos
Acidose Tubular Renal/fisiopatologia , Aldosterona/deficiência , Hiperpotassemia/etiologia , Pseudo-Hipoaldosteronismo/genética , Obstrução Ureteral/fisiopatologia , Acidose Tubular Renal/complicações , Aldosterona/metabolismo , Animais , Canais Epiteliais de Sódio/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Potenciais da Membrana , Néfrons/patologia , Potássio/urina , Insuficiência Renal Crônica/complicações , Sódio/metabolismo
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