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1.
Genes Dev ; 33(19-20): 1319-1345, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575677

RESUMO

There are now many reports of human kidney organoids generated via the directed differentiation of human pluripotent stem cells (PSCs) based on an existing understanding of mammalian kidney organogenesis. Such kidney organoids potentially represent tractable tools for the study of normal human development and disease with improvements in scale, structure, and functional maturation potentially providing future options for renal regeneration. The utility of such organotypic models, however, will ultimately be determined by their developmental accuracy. While initially inferred from mouse models, recent transcriptional analyses of human fetal kidney have provided greater insight into nephrogenesis. In this review, we discuss how well human kidney organoids model the human fetal kidney and how the remaining differences challenge their utility.


Assuntos
Rim/fisiologia , Modelos Biológicos , Organoides/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Rim/citologia , Rim/embriologia , Rim/crescimento & desenvolvimento , Organoides/citologia
2.
Nat Rev Nephrol ; 15(10): 625-640, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477915

RESUMO

Immunosenescence involves a series of ageing-induced alterations in the immune system and is characterized by two opposing hallmarks: defective immune responses and increased systemic inflammation. The immune system is modulated by intrinsic and extrinsic factors and undergoes profound changes in response to the ageing process. Immune responses are therefore highly age-dependent. Emerging data show that immunosenescence underlies common mechanisms responsible for several age-related diseases and is a plastic state that can be modified and accelerated by non-heritable environmental factors and pharmacological intervention. In the kidney, resident macrophages and fibroblasts are continuously exposed to components of the external environment, and the effects of cellular reprogramming induced by local immune responses, which accumulate with age, might have a role in the increased susceptibility to kidney disease among elderly individuals. Additionally, because chronic kidney disease, especially end-stage renal disease, is often accompanied by immunosenescence, which affects these patients independently of age, and many kidney diseases are strongly age-associated, treatment approaches that target immunosenescence might be particularly clinically relevant.


Assuntos
Envelhecimento/imunologia , Imunossenescência , Rim/imunologia , Animais , Humanos , Rim/crescimento & desenvolvimento
3.
Mar Biotechnol (NY) ; 21(5): 718-730, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31392593

RESUMO

The major causal factors for the irreversible decline in physical vitality during organismal aging are postulated to be a chronic state of cellular redox imbalance, metabolic toxicity, and impaired energy homeostasis. We assessed whether the relevant enzyme activity, oxidative stress, and intracellular ATP might be causally involved in the aging of short-lived Chlamys farreri (life span 4~5 years). A total of eight related biochemical and cellular indicators were chosen for the subsequent analysis. All the indicators were measured in seven different tissues from scallops aged one to four years, and our data support that the aging of C. farreri is associated with attenuated tissue enzyme activity as well as a decreased metabolic rate. Through principal component analysis, we developed an integrated vigor index for each tissue for comprehensive age-related fitness evaluation. Remarkably, all tissue-integrated vigor indexes significantly declined with age, and the kidney was observed to be the most representative tissue. Further transcriptional profiling of the enzymatic genes provided additional detail on the molecular responses that may underlie the corresponding biochemical results. Moreover, these critical molecular responses may be attributed to the conserved hierarchical regulators, e.g., FOXO, AMPKs, mTOR, and IGF1R, which were identified as potentially novel markers for chronic fitness decline with age in bivalves. The present study provides a systematic approach that could potentially benefit the global assessment of the aging process in C. farreri and provide detailed evaluation of the biochemical, cellular, and genetic indicators that might be involved. This information may assist in a better understanding of bivalve adaptability and life span.


Assuntos
Envelhecimento/genética , Bivalves/genética , Regulação da Expressão Gênica no Desenvolvimento , Transcriptoma , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Bivalves/crescimento & desenvolvimento , Bivalves/metabolismo , Metabolismo Energético/genética , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Perfilação da Expressão Gênica , Brânquias/crescimento & desenvolvimento , Brânquias/metabolismo , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Hepatopâncreas/crescimento & desenvolvimento , Hepatopâncreas/metabolismo , Homeostase/genética , Rim/crescimento & desenvolvimento , Rim/metabolismo , Especificidade de Órgãos , Oxirredução , Estresse Oxidativo , Análise de Componente Principal , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
4.
Reprod Toxicol ; 88: 91-128, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31386883

RESUMO

There is a growing demand for wild type mice and mouse models of disease that may be more representative of human conditions but there is little information on neonatal and juvenile mouse anatomy. This project produces sound and comprehensive histology background data on the developing neonatal mouse at different time points from Day 0 until Day 28. The work describes optimal methods for tissue harvesting, fixation and processing from the neonatal and juvenile mice which can be used in routine toxicology studies. A review of the available literature revealed inconsistencies in the developmental milestones reported in the mouse. Although it is true that the sequence of events during the development is virtually the same in mice and rats, important developmental milestones in the mouse often happen earlier than in the rat, and these species should not be used interchangeably.


Assuntos
Animais Recém-Nascidos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL/crescimento & desenvolvimento , Fatores Etários , Animais , Animais Recém-Nascidos/anatomia & histologia , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Feminino , Vesícula Biliar/anatomia & histologia , Vesícula Biliar/crescimento & desenvolvimento , Trato Gastrointestinal/anatomia & histologia , Trato Gastrointestinal/crescimento & desenvolvimento , Intestino Grosso/anatomia & histologia , Intestino Grosso/crescimento & desenvolvimento , Intestino Delgado/anatomia & histologia , Intestino Delgado/crescimento & desenvolvimento , Rim/anatomia & histologia , Rim/crescimento & desenvolvimento , Fígado/anatomia & histologia , Fígado/crescimento & desenvolvimento , Pulmão/anatomia & histologia , Pulmão/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL/anatomia & histologia , Ovário/anatomia & histologia , Ovário/crescimento & desenvolvimento , Ratos , Estômago/anatomia & histologia , Estômago/crescimento & desenvolvimento , Testículo/anatomia & histologia , Testículo/crescimento & desenvolvimento , Toxicologia/normas , Útero/anatomia & histologia , Útero/crescimento & desenvolvimento
5.
Ren Fail ; 41(1): 733-741, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31424299

RESUMO

Aim: Supplemental oxygen is often used to treat neonates with respiratory disorders. Human and animal studies have demonstrated that neonatal hyperoxia increases oxidative stress and induces damage and collagen deposition in kidney during the perinatal period. Cathelicidin LL-37 is one important group of human antimicrobial peptides which exhibits antioxidant activity and its overexpression resists hyperoxia-induced oxidative stress. This study was designed to evaluate the protective effects of cathelicidin in hyperoxia-induced kidney injury in newborn rats. Methods: Sprague-Dawley rat pups were reared in either room air (RA) or hyperoxia (85% O2) and were randomly treated with low-dose (4 mg/kg) and high-dose (8 mg/kg) cathelicidin in normal saline (NS) administered intraperitoneally on postnatal days 1-6. The following six groups were obtained: RA + NS, RA + low-dose cathelicidin, RA + high-dose cathelicidin, O2 + NS, O2 + low-dose cathelicidin, and O2 + high-dose cathelicidin. Kidneys were taken for Western blot and histological analyses on postnatal day 7. Results: The hyperoxia-reared rats exhibited significantly lower body weights and anti-inflammatory M2 macrophages, but the kidney injury scores, oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells, pro-inflammatory M1 macrophages, collagen deposition, and NF-κB expression were higher than did the RA-reared rats. Conclusions: Cathelicidin treatment attenuated kidney injury as evidenced by lower kidney injury scores, 8-OHdG-positive cells, collagen deposition, and reversion of hyperoxia-induced M1/M2 macrophage polarization. The role of Cathelicidin in ameliorates kidney injury of the hyperoxia newborn rats was accompanied by decreased NF-κB expression, which probably through the modulating NF-κB activity in the kidney.


Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Hiperóxia/complicações , Nefropatias/prevenção & controle , Oxigenoterapia/efeitos adversos , Oxigênio/efeitos adversos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/crescimento & desenvolvimento , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Ativação de Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/administração & dosagem , Oxigenoterapia/métodos , Gravidez , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Transdução de Sinais/efeitos dos fármacos
6.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(3): 291-299, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31282321

RESUMO

Objective To induce adipose-derived stem cells (ADSCs) to differentiate into intermediate mesoderm (IM)-like cells in vitro,with IM-like cells for recellularizing kidney scaffolds,and then to obtain a tissue-engineering kidney with renal structures and functions through co-culture.Methods After inguinal fat pads of Wistar rats were surgically harvested,the primary ADSCs were isolated,induced,and cultured for stem cell identification. ADSCs were inducted to differentiate into IM-like cells by adding glycogen synthase kinase-3 inhibitor (CHIR99021) and fibroblast growth factor 9 (FGF9) at different stages. Seven days later,the IM-like cells were identified. The induced IM-like cells and well-prepared kidney decellularized scaffolds were co-cultured for 10 days to obtain recellularized tissue-engineered kidneys and their differentiation was identified.Results The ADSCs harvested had osteogenic and adipogenic abilities and could express the stem cell surface markers. After 7 days of in vitro induction,the positive expressions of odd-skipped related 1 and paired-box 2 were observed in IM-like cells by immunofluorescence technique. After 10 days of co-culture with kidney decellularized scaffolds,the positive expressions of Wilms'tumor 1,GATA-binding protein-3,and E-cadherin were observed by immunofluorescence technique.Conclusion ADSCs can be induced into IM-like cells,and renal cell differentiation can be observed through combining the induced IM-like cells with kidney decellularized scaffolds.


Assuntos
Rim/crescimento & desenvolvimento , Mesoderma/citologia , Regeneração , Células-Tronco/citologia , Engenharia Tecidual , Tecido Adiposo , Animais , Diferenciação Celular , Células Cultivadas , Ratos , Ratos Wistar , Tecidos Suporte
7.
Am J Physiol Regul Integr Comp Physiol ; 316(5): R640-R650, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30943054

RESUMO

Formation of the metanephric kidney requires coordinated interaction among the stroma, ureteric bud, and cap mesenchyme. The transcription factor Foxd1, a specific marker of renal stromal cells, is critical for normal kidney development. The prorenin receptor (PRR), a receptor for renin and prorenin, is also an accessory subunit of the vacuolar proton pump V-ATPase. Global loss of PRR is embryonically lethal in mice, indicating an essential role of the PRR in embryonic development. Here, we report that conditional deletion of the PRR in Foxd1+ stromal progenitors in mice (cKO) results in neonatal mortality. The kidneys of surviving mice show reduced expression of stromal markers Foxd1 and Meis1 and a marked decrease in arterial and arteriolar development with the subsequent decreased number of glomeruli, expansion of Six2+ nephron progenitors, and delay in nephron differentiation. Intrarenal arteries and arterioles in cKO mice were fewer and thinner and showed a marked decrease in the expression of renin, suggesting a central role for the PRR in the development of renin-expressing cells, which in turn are essential for the proper formation of the renal arterial tree. We conclude that stromal PRR is crucial for the appropriate differentiation of the renal arterial tree, which in turn may restrict excessive expansion of nephron progenitors to promote a coordinated and proper morphogenesis of the nephrovascular structures of the mammalian kidney.


Assuntos
Rim/crescimento & desenvolvimento , Néfrons/metabolismo , Organogênese/fisiologia , Receptores de Superfície Celular/metabolismo , Animais , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica/fisiologia , Rim/metabolismo , Camundongos Transgênicos , Renina/metabolismo , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo
8.
Nat Biotechnol ; 37(3): 303-313, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833775

RESUMO

Adult stem cell-derived organoids are three-dimensional epithelial structures that recapitulate fundamental aspects of their organ of origin. We describe conditions for the long-term growth of primary kidney tubular epithelial organoids, or 'tubuloids'. The cultures are established from human and mouse kidney tissue and can be expanded for at least 20 passages (>6 months) while retaining a normal number of chromosomes. In addition, cultures can be established from human urine. Human tubuloids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. We apply tubuloids to model infectious, malignant and hereditary kidney diseases in a personalized fashion. BK virus infection of tubuloids recapitulates in vivo phenomena. Tubuloids are established from Wilms tumors. Kidney tubuloids derived from the urine of a subject with cystic fibrosis allow ex vivo assessment of treatment efficacy. Finally, tubuloids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active (trans-)epithelial transport function.


Assuntos
Rim/citologia , Néfrons/citologia , Organoides/citologia , Medicina de Precisão , Adulto , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Animais , Técnicas de Cultura de Células/métodos , Diferenciação Celular/genética , Humanos , Rim/crescimento & desenvolvimento , Nefropatias , Camundongos , Néfrons/metabolismo , Organoides/metabolismo , Urina/citologia
9.
J Am Soc Nephrol ; 30(4): 594-609, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30850438

RESUMO

BACKGROUND: Cytosine methylation of regulatory regions, such as promoters and enhancers, plays a key role in regulating gene expression, however, its role in kidney development has not been analyzed. METHODS: To identify functionally important epigenome-modifying enzymes and genome regions where methylation modifications are functionally important for kidney development, we performed genome-wide methylation analysis, expression profiling, and systematic genetic targeting of DNA methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) and Ten-eleven translocation methylcytosine hydroxylases (Tet2) in nephron progenitor cells (Six2 Cre) in mice. RESULTS: Genome-wide methylome analysis indicated dynamic changes on promoters and enhancers during development. Six2 Cre Dnmt3a f/f, Six2 Cre Dnmt3b f/f, and Six2 Cre Tet2 f/f mice showed no significant structural or functional renal abnormalities. In contrast, Six2 Cre Dnmt1 f/f mice died within 24 hours of birth, from a severe kidney developmental defect. Genome-wide methylation analysis indicated a marked loss of methylation of transposable elements. RNA sequencing detected endogenous retroviral transcripts. Expression of intracellular viral sensing pathways (RIG-I), early embryonic, nonrenal lineage genes and increased cell death contributed to the phenotype development. In podocytes, loss of Dnmt1, Dnmt3a, Dnmt3b, or Tet2 did not lead to functional or structural differences at baseline or after toxic injury. CONCLUSIONS: Genome-wide cytosine methylation and gene expression profiling showed that by silencing embryonic, nonrenal lineage genes and transposable elements, DNMT1-mediated cytosine methylation is essential for kidney development.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA , Proteínas de Homeodomínio/genética , Rim/crescimento & desenvolvimento , Células-Tronco/fisiologia , Fatores de Transcrição/genética , Animais , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Elementos de DNA Transponíveis , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Expressão Gênica , Inativação Gênica , Rim/enzimologia , Masculino , Camundongos , Podócitos/citologia , Podócitos/fisiologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , RNA Viral/análise , Análise de Sequência de RNA , Células-Tronco/citologia , Transcriptoma
10.
Nat Commun ; 10(1): 451, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723213

RESUMO

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor. Here, conversely, we show that mouse PSCs can efficiently differentiate into the metanephric mesenchyme in rat, allowing the generation of mouse PSC-derived kidney in anephric Sall1 mutant rat. Glomerular epithelium and renal tubules in the kidneys are entirely composed of mouse PSC-derived cells expressing key functional markers. Importantly, the ureter-bladder junction is normally formed. These data provide proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation.


Assuntos
Falência Renal Crônica/terapia , Células-Tronco Pluripotentes/transplante , Fatores de Transcrição/metabolismo , Animais , Blastocisto/citologia , Blastocisto/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Rim/crescimento & desenvolvimento , Rim/metabolismo , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Masculino , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Ratos , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Transplante Homólogo
11.
Nephron ; 142(2): 117-124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30726854

RESUMO

An infant is described as "preterm" if they are born before 37 weeks of gestation. As nephrogenesis does not complete until 36 weeks of gestation, premature infants are often born with underdeveloped kidneys. Current evidence strongly suggests that this leaves those born prematurely more susceptible to developing kidney-related conditions later in life. Although the incidence of premature birth steadily increases each year in the United Kingdom, reports of perinatal death following preterm labour are falling. This is mainly attributed to the development of antenatal drugs, such as tocolytics, corticosteroids and antibiotics. Though these drugs have effectively reduced the incidence of premature-birth-related deaths, evidence suggests that they may be nephrotoxic. This review will describe the experimental evidence that some therapeutics are disadvantageous to kidney functions later on in life.


Assuntos
Corticosteroides/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antibacterianos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Rim/fisiopatologia , Tocolíticos/efeitos adversos , Corticosteroides/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Rim/crescimento & desenvolvimento , Reino Unido
12.
PLoS Biol ; 17(2): e3000152, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30789893

RESUMO

The current understanding of mammalian kidney development is largely based on mouse models. Recent landmark studies revealed pervasive differences in renal embryogenesis between mouse and human. The scarcity of detailed gene expression data in humans therefore hampers a thorough understanding of human kidney development and the possible developmental origin of kidney diseases. In this paper, we present a single-cell transcriptomics study of the human fetal kidney. We identified 22 cell types and a host of marker genes. Comparison of samples from different developmental ages revealed continuous gene expression changes in podocytes. To demonstrate the usefulness of our data set, we explored the heterogeneity of the nephrogenic niche, localized podocyte precursors, and confirmed disease-associated marker genes. With close to 18,000 renal cells from five different developmental ages, this study provides a rich resource for the elucidation of human kidney development, easily accessible through an interactive web application.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Rim/metabolismo , Organogênese/genética , Podócitos/metabolismo , Transcriptoma , Diferenciação Celular , Linhagem da Célula/genética , Conjuntos de Dados como Assunto , Feminino , Desenvolvimento Fetal , Feto , Perfilação da Expressão Gênica , Ontologia Genética , Idade Gestacional , Humanos , Rim/citologia , Rim/crescimento & desenvolvimento , Masculino , Anotação de Sequência Molecular , Podócitos/citologia , Análise de Célula Única
14.
Nat Commun ; 10(1): 239, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651543

RESUMO

Branching patterns and regulatory networks differ between branched organs. It has remained unclear whether a common regulatory mechanism exists and how organ-specific patterns can emerge. Of all previously proposed signalling-based mechanisms, only a ligand-receptor-based Turing mechanism based on FGF10 and SHH quantitatively recapitulates the lung branching patterns. We now show that a GDNF-dependent ligand-receptor-based Turing mechanism quantitatively recapitulates branching of cultured wildtype and mutant ureteric buds, and achieves similar branching patterns when directing domain outgrowth in silico. We further predict and confirm experimentally that the kidney-specific positive feedback between WNT11 and GDNF permits the dense packing of ureteric tips. We conclude that the ligand-receptor based Turing mechanism presents a common regulatory mechanism for lungs and kidneys, despite the differences in the molecular implementation. Given its flexibility and robustness, we expect that the ligand-receptor-based Turing mechanism constitutes a likely general mechanism to guide branching morphogenesis and other symmetry breaks during organogenesis.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Rim/crescimento & desenvolvimento , Modelos Biológicos , Organogênese , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Wnt/metabolismo , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Simulação por Computador , Embrião de Mamíferos , Retroalimentação Fisiológica , Feminino , Processamento de Imagem Assistida por Computador , Rim/diagnóstico por imagem , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Técnicas de Cultura de Órgãos , Transdução de Sinais/fisiologia , Imagem com Lapso de Tempo/métodos , Tomografia Óptica/métodos
15.
Folia Morphol (Warsz) ; 78(1): 114-123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30106465

RESUMO

BACKGROUND: Kidney has long been thought to be a body's largest organ of elimination for maintaining acid-base balance. In recent years, the research on kidneys has mainly focused on the structural characteristics of the kidney of single age group animals. In this paper we used histological and immunohistochemical methods to observe and compare the structure characteristics of yak kidney and the expression of epidermal growth factor receptor (EGFR), bone morphogenetic protein-2 (BMP-2) and p53 in the kidney of yaks of three different age groups. The aim of the study was to investigate histological characteristics of age-related chan- ges in the kidney of yak and expression and localisation of kidney-related factors. MATERIALS AND METHODS: Fifteen healthy male and female yaks from highland plateaus (three groups: newborn, adult and old yaks, n = 5 per group). Histo- logical methods were used to compare the relevant characteristics of the kidney of yaks. The immunohistochemistry method was used to observe the expression and localisation of EGFR, BMP-2, and p53 of the kidney of different ages, and the optical density value was measured and analysed by using image analysis software. RESULTS: This is an overall observation of the kidney tissue section, which includes the surface of the renal capsule and the internal parenchyma. In the renal parenchyma, there are renal corpuscles, renal tubules. The internal substance included cortex and medulla, which were bounded by the arched artery. In the cortex, there were renal corpuscles, convoluted part of renal tubules (proximal convoluted tubule and distal convoluted tubule) and collecting tubules. The medulla included straight parts of renal tubules (proximal straight tubule and distal straight tubule), thin segments and collecting tubules. It was observed that the organisational structure of the kidney of yaks did not change with age, but the degree of development of the internal structure (glomeruli, renal tubules and collecting tubules) of the kidney changed with age. Immunohistochemical results demonstrated that EGFR and BMP-2-positive reaction in the newborn group was mainly distributed in the proximal tubule epithelial cells, and widely distributed in the adult and old groups. However, the p53-positive reaction was widely distributed in the newborn, adult and old groups. CONCLUSIONS: The results revealed that the kidney structure tended to be com- pleted with age, and the function of the kidney gradually improved. EGFR and BMP-2 had the effect of promoting kidney development. However, p53 had been widely distributed in the newborn kidney of the yaks. It is suggested that p53 had been involved in cell migration and metabolic differentiation and self-renewal in the new stage.


Assuntos
Bovinos/crescimento & desenvolvimento , Bovinos/metabolismo , Rim/crescimento & desenvolvimento , Rim/metabolismo , Animais , Proteína Morfogenética Óssea 2/biossíntese , Receptores ErbB/biossíntese , Feminino , Masculino , Proteína Supressora de Tumor p53/biossíntese
16.
Clin Exp Nephrol ; 23(4): 537-543, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30353264

RESUMO

BACKGROUND: We recently demonstrated that preterm neonates have higher urinary angiotensinogen (AGT) levels than full-term neonates. Here, we tested the hypothesis that enhanced neonatal AGT expression is associated with intrarenal renin-angiotensin system (RAS) status during kidney development. METHODS: We prospectively recruited neonates born at our hospital and healthy children with minor glomerular abnormalities between April 2013 and March 2017. We measured neonatal plasma and urinary AGT levels at birth and 1 year later and assessed renal AGT expression in kidney tissues from neonates and healthy children using immunohistochemical (IHC) analysis. RESULTS: Fifty-four neonates and eight children were enrolled. Although there were no changes in plasma AGT levels, urinary AGT levels were significantly decreased 1 year after birth. Urinary AGT levels at birth were inversely correlated with gestational age, and urinary AGT levels at birth and 1 year later were inversely correlated with estimated glomerular filtration rate 1 year after birth. IHC analysis showed that renal AGT expression in neonates was higher than that in healthy children and inversely correlated with gestational age. CONCLUSIONS: Enhanced AGT expression and urinary AGT excretion may reflect intrarenal RAS activation associated with kidney development in utero.


Assuntos
Angiotensinogênio/sangue , Angiotensinogênio/urina , Rim/crescimento & desenvolvimento , Angiotensinogênio/metabolismo , Biópsia , Criança , Pré-Escolar , Creatinina/urina , Feminino , Idade Gestacional , Taxa de Filtração Glomerular , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Rim/patologia , Rim/fisiologia , Glomérulos Renais/anormalidades , Masculino , Parto , Estudos Prospectivos
17.
J Exp Zool A Ecol Integr Physiol ; 331(1): 38-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30362660

RESUMO

Allometric equations represent relationships between morphological/physiological traits and body mass Y = aMb , where Y is the trait, a is elevation, b is the exponent describing the shape of the line, and M is body mass. We measured visceral organ masses in hatchling alligators (Alligator mississippiensis) from five clutches from approximately 45 to 500 g wet body mass. The interaction between initial egg mass and clutch identity was significant for initial hatchling mass, but only egg mass, not clutch, had a significant effect on initial snout-vent and head length. Kidney and liver mass showed biphasic scaling with body mass, as determined by "breakpoint" analyses, with the breakpoint at 120 g wet body mass. Kidney and liver wet mass showed slopes b > 1.0 as animals increased approximately 45-120 g, with significantly lower b approximately 0.8-0.9 for alligators 120-500 g. Within kidney and liver mass, below and above the breakpoint, organ mass slopes tended to be similar across clutches. Lung and heart wet mass did not show biphasic scaling, with b approximately 0.8-0.9. Within lung and heart mass, clutches had statistically identical slopes. Combined clutch data for wet mass showed distinct regressions with b > 1.4 for approximately 45-120 g alligators' kidney and liver mass, compared with approximately 120-500 g alligators' kidney, liver, lung, and heart mass b < 1.0. Alligators show rapid kidney and liver growth following hatching, with higher rates than lung or heart tissue. Clutch, egg mass, and hatchling size influence organ size, and each factor should be accounted for in future studies exploring reptile morphology and physiology to assess environmental versus clutch contributions.


Assuntos
Jacarés e Crocodilos/anatomia & histologia , Coração/anatomia & histologia , Rim/anatomia & histologia , Fígado/anatomia & histologia , Pulmão/anatomia & histologia , Jacarés e Crocodilos/crescimento & desenvolvimento , Animais , Tamanho Corporal , Feminino , Coração/crescimento & desenvolvimento , Rim/crescimento & desenvolvimento , Fígado/crescimento & desenvolvimento , Pulmão/crescimento & desenvolvimento , Tamanho do Órgão
18.
J Cell Physiol ; 234(3): 2837-2850, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30317563

RESUMO

The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ-dependent process. In addition, the PPARγ antagonist GW9662, which can depress total-PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d-PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal-clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria-induced crystal retention. This detrimental effect was partially reversed by 15d-PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells.


Assuntos
Oxalato de Cálcio/metabolismo , Transdiferenciação Celular/genética , Cálculos Renais/genética , PPAR gama/genética , Anilidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Cães , Humanos , Rim/efeitos dos fármacos , Rim/crescimento & desenvolvimento , Rim/patologia , Cálculos Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Células Madin Darby de Rim Canino , PPAR gama/antagonistas & inibidores , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia
19.
Biochim Biophys Acta Gene Regul Mech ; 1862(1): 58-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30416088

RESUMO

Emerging evidence from recent studies has unraveled the roles of long noncoding RNAs (lncRNAs) in the function of various tissues. However, little is known about the roles of lncRNAs in kidney development. In our present study, we aimed to identify functional lncRNAs in one of the three lineages of kidney progenitor cells, i.e., metanephric mesenchymal (MM) cells. We conducted comprehensive analyses of the chromatin signature and transcriptome by RNA-seq and ChIP-seq. We found seventeen lncRNAs that were expressed specifically in MM cells with an active chromatin signature, while remaining silenced in a bivalent chromatin state in non-MM cells. Out of these MM specific lncRNAs, we identified a lncRNA, Gm29418, in a distal enhancer region of Six2, a key regulatory gene of MM cells. We further identified three transcript variants of Gm29418 by Rapid Amplification of cDNA Ends (RACE), and confirmed that the transcription-start-sites (TSSs) of these variants were consistent with the result of Cap Analysis Gene Expression (CAGE). In support of the enhancer-like function of Gm29418 on Six2 expression, we found that knock-down of Gm29418 by two independent anti-sense locked nucleic acid (LNA) phosphorothioate gapmers suppressed Six2 mRNA expression levels in MM cells. We also found that over-expression of Gm29418 led to an increase in Six2 mRNA expression levels in a mouse MM cell line. In conclusion, we identified a lncRNA, Gm29418, in nephron progenitor cells that has an enhancer-like function on a key regulatory gene, Six2.


Assuntos
Rim/crescimento & desenvolvimento , Néfrons/citologia , RNA Longo não Codificante/fisiologia , Células-Tronco/metabolismo , Animais , Cromatina , Proteínas de Homeodomínio/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Transcriptoma
20.
Am J Med Genet A ; 179(1): 71-77, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422383

RESUMO

Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural kidney defects occur at an increased frequency in Jacobsen syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.1 Mb "critical region" for kidney defects in Jacobsen syndrome, which spans ~50 genes. We demonstrate that gene-targeted deletion of Ets-1 in mice results in some of the most common congenital kidney defects occurring in Jacobsen syndrome, including: duplicated kidney, hypoplastic kidney, and dilated renal pelvis and calyces. Taken together, our results implicate Ets-1 in normal mammalian kidney development and, potentially, in the pathogenesis of some of the most common types of human structural kidney defects.


Assuntos
Síndrome da Deleção Distal 11q de Jacobsen/genética , Rim/patologia , Proteína Proto-Oncogênica c-ets-1/genética , Animais , Cromossomos Humanos Par 11 , Modelos Animais de Doenças , Deleção de Genes , Marcação de Genes , Predisposição Genética para Doença , Humanos , Síndrome da Deleção Distal 11q de Jacobsen/patologia , Rim/anormalidades , Rim/crescimento & desenvolvimento , Camundongos , Deleção de Sequência/genética
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