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2.
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
3.
J Morphol ; 280(10): 1452-1461, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313860

RESUMO

Salamanders possess kidneys with two distinct regions: a caudal pelvic portion and cranial genital portion. Nephrons of the pelvic region are responsible for urine formation and transport. Nephrons of the genital region transport sperm from testes to Wolffian ducts; however, nephrons of the genital region possess all the same functional regions found in pelvic kidney nephrons that are involved with urine formation and transport (renal corpuscles, proximal tubules, distal tubules, and collecting ducts). Morphological similarities between pelvic and genital regions stimulated past researchers to hypothesize that nephrons of genital kidneys possess dual function; that is, sperm transport and urine formation/transport. Considering size of glomeruli is directly related to the total amount of blood plasma filtered into the Bowman's space, we tested the hypothesis that nephrons of genital kidneys have reduced urine formation function by comparing glomerular size between nephrons of pelvic and genital kidney regions in Eurycea longicauda with general histological techniques. Light microscopy analysis revealed that glomeruli of pelvic kidneys were significantly larger than those measured from genital kidneys. Transmission electron microscopy analysis also revealed modifications in genital kidney nephrons when compared to pelvic kidney nephrons that suggested a decrease in urine formation function in genital kidneys. Such modifications included a decrease in basal and lateral plasma membrane folding in genital kidney proximal and distal tubules compared to that of pelvic kidney proximal and distal tubules. Genital kidney proximal tubules were also ciliated, which was not observed in pelvic kidney proximal tubules. In conclusion, although structurally similar at the histological level, it appears that nephrons of genital kidneys have decreased urine formation function based on glomerular size comparison and nephron ultrastructure.


Assuntos
Néfrons/ultraestrutura , Transporte Espermático , Urodelos/fisiologia , Animais , Masculino , Microscopia Eletrônica de Transmissão , Néfrons/fisiologia , Testículo/fisiologia , Urodelos/anatomia & histologia
4.
Korean J Intern Med ; 34(3): 470-479, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31048657

RESUMO

Many cells in the nephron release extracellular vesicles (EVs). EVs envelop nucleic acids, proteins, and lipids. The surfaces of EVs express donor cell-specific markers, ligands, and major histocompatibility complex molecules. They are involved in cell-to-cell communication, immune modulation, and the removal of unwanted materials from cells. EVs have been studied as biomarkers of specific diseases and have potential therapeutic applications. Recent research has emphasized the functions of EVs in the kidney. This review provides an overview of recent findings related to the roles of EVs in the nephron, and their utility as biomarkers and therapeutic factors in renal disease.


Assuntos
Vesículas Extracelulares/metabolismo , Nefropatias/metabolismo , Néfrons/fisiologia , Biomarcadores/urina , Portadores de Fármacos , Humanos
5.
PLoS One ; 14(4): e0215139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30978219

RESUMO

Primed nephron progenitor cells (NPCs) appear in metanephric mesenchyme by E11.5 and differentiate in response to the inductive WNT9b signal from the ureteric bud. However, the NPC WNT-receptor complex is unknown. We obtained M15 cells from E10.5 mesonephric mesenchyme and systematically analyzed components required for canonical WNT9b-responsiveness. When M15 cells were transfected with a ß-catenin luciferase reporter plasmid, exposure to recombinant WNT9b resulted in minimal luciferase activity. We then analyzed mRNA-expression of WNT-pathway components and identified Fzd1-6 and Lrp6 transcripts but not Rspo1. When M15 cells were treated with recombinant RSPO1 the response to transfected WNT9b was augmented 4.8-fold. Co-transfection of M15 cells with Fzd5 (but no other Fzd family member) further increased the WNT9b signal to 16.8-fold and siRNA knockdown of Fzd5 reduced the signal by 52%. Knockdown of Lrp6 resulted in 60% WNT9b signal reduction. We confirmed Fzd5, Lrp6 and Rspo1 mRNA expression in CITED1(+) NPCs from E15.5 embryonic mouse kidney. Thus, while many WNT signaling-pathway components are present by E10.5, optimum responsiveness of E11.5 cap mesenchyme requires that NPCs acquire RSPO1, FZD5 and LRP6.


Assuntos
Mesoderma/fisiologia , Néfrons/fisiologia , Células-Tronco/fisiologia , Proteínas Wnt/metabolismo , Animais , Células Cultivadas , Mesoderma/citologia , Camundongos , Néfrons/citologia , Transdução de Sinais , Células-Tronco/citologia , Proteínas Wnt/genética , beta Catenina/metabolismo
6.
Kidney Int ; 95(5): 1153-1166, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30827514

RESUMO

All nephrons in the mammalian kidney arise from a transient nephron progenitor population that is lost close to the time of birth. The generation of new nephron progenitors and their maintenance in culture are central to the success of kidney regenerative strategies. Using a lentiviral screening approach, we previously generated a human induced nephron progenitor-like state in vitro using a pool of six transcription factors. Here, we sought to develop a more efficient approach for direct reprogramming of human cells that could be applied in vivo. PiggyBac transposons are a non-viral integrating gene delivery system that is suitable for in vivo use and allows for simultaneous delivery of multiple genes. Using an inducible piggyBac transposon system, we optimized a protocol for the direct reprogramming of HK2 cells to induced nephron progenitor-like cells with expression of only 3 transcription factors (SNAI2, EYA1, and SIX1). Culture in conditions supportive of the nephron progenitor state further increased the expression of nephron progenitor genes. The refined protocol was then applied to primary human renal epithelial cells, which integrated into developing nephron structures in vitro and in vivo. Such inducible reprogramming to nephron progenitor-like cells could facilitate direct cellular reprogramming for kidney regeneration.


Assuntos
Reprogramação Celular/genética , Elementos de DNA Transponíveis/genética , Engenharia Genética/métodos , Néfrons/fisiologia , Regeneração/genética , Células Cultivadas , Técnicas de Transferência de Genes , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Cultura Primária de Células , Proteínas Tirosina Fosfatases/genética , Fatores de Transcrição da Família Snail/genética
7.
PLoS Comput Biol ; 15(2): e1006108, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30802242

RESUMO

We have developed the first computational model of solute and water transport from Bowman space to the papillary tip of the nephron of a human kidney. The nephron is represented as a tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type. The model is formulated for steady state, and consists of a large system of coupled ordinary differential equations and algebraic equations. Model solution describes luminal fluid flow, hydrostatic pressure, luminal fluid solute concentrations, cytosolic solute concentrations, epithelial membrane potential, and transcellular and paracellular fluxes. We found that if we assume that the transporter density and permeabilities are taken to be the same between the human and rat nephrons (with the exception of a glucose transporter along the proximal tubule and the H+-pump along the collecting duct), the model yields segmental deliveries and urinary excretion of volume and key solutes that are consistent with human data. The model predicted that the human nephron exhibits glomerulotubular balance, such that proximal tubular Na+ reabsorption varies proportionally to the single-nephron glomerular filtration rate. To simulate the action of a novel diabetic treatment, we inhibited the Na+-glucose cotransporter 2 (SGLT2) along the proximal convoluted tubule. Simulation results predicted that the segment's Na+ reabsorption decreased significantly, resulting in natriuresis and osmotic diuresis.


Assuntos
Biologia Computacional/métodos , Néfrons/metabolismo , Néfrons/fisiologia , Transporte Biológico/fisiologia , Simulação por Computador , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/fisiologia , Modelos Biológicos , Proteínas Carreadoras de Solutos/metabolismo
8.
Transpl Int ; 32(6): 563-570, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30710378

RESUMO

It is difficult to restore kidney function following chronic kidney damage. Although dialysis is currently used to treat patients with chronic kidney disease, it does not cure the disease, while severely restricting the patient's daily and social activities. Kidney transplantation is an alternative and curative therapy, but donor numbers remain limited. However, the generation of kidney organoids from human induced pluripotent stem cells represents an important recent advance in regenerative medicine. Kidney organoids are expected to be used for disease modeling and drug discovery, and may eventually be applicable for transplantation. In this review, we describe the current status of kidney organoids and discuss the hurdles that need to be overcome to generate transplantable artificial kidneys.


Assuntos
Células-Tronco Pluripotentes Induzidas , Transplante de Rim , Rim/fisiologia , Rim/fisiopatologia , Rins Artificiais , Organoides , Animais , Humanos , Rim/irrigação sanguínea , Néfrons/fisiologia , Células-Tronco
9.
Elife ; 82019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30616715

RESUMO

Amphibians and fish have the ability to regenerate numerous tissues, whereas mammals have a limited regenerative capacity. Despite numerous developmental genes becoming reactivated during regeneration, an extensive analysis is yet to be performed on whether highly regenerative animals utilize unique cis-regulatory elements for the reactivation of genes during regeneration and how such cis-regulatory elements become activated. Here, we screened regeneration signal-response enhancers at the lhx1 locus using Xenopus and found that the noncoding elements conserved from fish to human function as enhancers in the regenerating nephric tubules. A DNA-binding motif of Arid3a, a component of H3K9me3 demethylases, was commonly found in RSREs. Arid3a binds to RSREs and reduces the H3K9me3 levels. It promotes cell cycle progression and causes the outgrowth of nephric tubules, whereas the conditional knockdown of arid3a using photo-morpholino inhibits regeneration. These results suggest that Arid3a contributes to the regeneration of nephric tubules by decreasing H3K9me3 on RSREs.


Assuntos
Evolução Biológica , Sequência Conservada , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos , Túbulos Renais/fisiologia , Néfrons/fisiologia , Regeneração/fisiologia , Fatores de Transcrição/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus/fisiologia , Animais , Animais Geneticamente Modificados , Ciclo Celular , Cromatina/metabolismo , Peixes , Humanos , Nefrectomia
10.
J Am Soc Nephrol ; 30(1): 63-78, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30518531

RESUMO

BACKGROUND: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear. METHODS: We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development. RESULTS: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression. CONCLUSIONS: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , Rim/embriologia , Organogênese/genética , Células-Tronco/citologia , Animais , Diferenciação Celular/genética , Células Cultivadas , Metilação de DNA , Regulação da Expressão Gênica no Desenvolvimento/genética , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Néfrons/citologia , Néfrons/fisiologia , Ratos , Ratos Wistar , Sensibilidade e Especificidade , Células-Tronco/fisiologia
11.
Semin Cell Dev Biol ; 91: 153-168, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30184476

RESUMO

Decades of research into the molecular and cellular regulation of kidney morphogenesis in rodent models, particularly the mouse, has provided both an atlas of the mammalian kidney and a roadmap for recreating kidney cell types with potential applications for the treatment of kidney disease. With advances in both our capacity to maintain nephron progenitors in culture, reprogram to kidney cell types and direct the differentiation of human pluripotent stem cells to kidney endpoints, renal regeneration via cellular therapy or tissue engineering may be possible. Human kidney models also have potential for disease modelling and drug screening. Such applications will rely upon the accuracy of the model at the cellular level and the capacity for stem-cell derived kidney tissue to recapitulate both normal and diseased kidney tissue. In this review, we will discuss the available cell sources, how well they model the human kidney and how far we are from application either as models or for tissue engineering.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Rim/fisiologia , Néfrons/fisiologia , Regeneração , Insuficiência Renal Crônica/terapia , Animais , Diferenciação Celular , Humanos , Rim/citologia , Néfrons/citologia , Células-Tronco Pluripotentes/citologia , Insuficiência Renal Crônica/fisiopatologia , Engenharia Tecidual/métodos
12.
Sci Rep ; 8(1): 14919, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297790

RESUMO

Kidney regeneration from pluripotent stem cells is receiving a lot of attention because limited treatments are currently available for chronic kidney disease (CKD). It has been shown that uremic state in CKD is toxic to somatic stem/progenitor cells, such as endothelial progenitor and mesenchymal stem cells, affecting their differentiation and angiogenic potential. Recent studies reported that specific abnormalities caused by the non-inherited disease are often retained in induced pluripotent stem cell (iPSC)-derived products obtained from patients. Thus, it is indispensable to first assess whether iPSCs derived from patients with CKD due to non-inherited disease (CKD-iPSCs) have the ability to generate kidneys. In this study, we generated iPSCs from patients undergoing haemodialysis due to diabetes nephropathy and glomerulonephritis (HD-iPSCs) as representatives of CKD-iPSCs or from healthy controls (HC-iPSCs). HD-iPSCs differentiated into nephron progenitor cells (NPCs) with similar efficiency to HC-iPSCs. Additionally, HD-iPSC-derived NPCs expressed comparable levels of NPC markers and differentiated into vascularised glomeruli upon transplantation into mice, as HC-iPSC-derived NPCs. Our results indicate the potential of HD-iPSCs as a feasible cell source for kidney regeneration. This is the first study paving the way for CKD patient-stem cell-derived kidney regeneration, emphasising the potential of CKD-iPSCs.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Rim/citologia , Rim/fisiologia , Regeneração , Insuficiência Renal Crônica/terapia , Animais , Diferenciação Celular , Células Cultivadas , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/terapia , Glomerulonefrite/fisiopatologia , Glomerulonefrite/terapia , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Rim/fisiopatologia , Camundongos , Néfrons/citologia , Néfrons/fisiologia , Néfrons/fisiopatologia , Diálise Renal , Insuficiência Renal Crônica/fisiopatologia
13.
Proc Natl Acad Sci U S A ; 115(23): 5998-6003, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29784808

RESUMO

Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one Tsc1 allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both Tsc1 alleles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor.


Assuntos
Néfrons , Organogênese/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Néfrons/química , Néfrons/citologia , Néfrons/crescimento & desenvolvimento , Néfrons/fisiologia , Serina-Treonina Quinases TOR/genética , Proteína 1 do Complexo Esclerose Tuberosa
14.
Adv Physiol Educ ; 42(2): 192-199, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29616568

RESUMO

The purpose of this study is to see whether a large drawing of a nephron helped medical students in self-directed learning groups learn renal physiology, histology, and pharmacology before discussing clinical cases. The end points were the grades on the renal examination and a student survey. The classes in the fall of 2014 and 2015 used the drawing, but not those of 2012 and 2013. The Charles E. Schmidt College of Medicine at Florida Atlantic University is a newly formed Florida medical school, which enrolled its first class in the fall of 2011. The school relies on self-directed problem-based learning in year 1 and changes over to a case inquiry method in the latter part of year 1 and throughout year 2. At the start of the renal course, each student group received a poster of a nephron with the objective of learning the cell functions of the different nephron parts. During the first year of using the drawing, there was no improvement in grades. After a student suggested adjustment to the drawing, there was a statistically significant difference in the total test score in the second year ( P < 0.001). An unexpected finding was lower grades in all 4 yr in the area of acid-base balance and electrolytes compared with the other four areas tested. In the survey, the students found the drawing useful.


Assuntos
Histologia/educação , Néfrons/fisiologia , Farmacologia/educação , Fisiologia/educação , Aprendizagem Baseada em Problemas/métodos , Estudantes de Medicina , Educação Médica/métodos , Avaliação Educacional , Feminino , Humanos , Rim/fisiologia , Masculino , Néfrons/anatomia & histologia , Estudos Retrospectivos , Ensino , Adulto Jovem
15.
Dev Biol ; 440(1): 13-21, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29705331

RESUMO

Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand signaling through one transcription factor promoted two seemingly contradictory cellular processes was unclear. In this study, we show that Wnt9b/beta-catenin signaling alone is sufficient to promote both renewal and differentiation. Moreover, we show that discrete levels of beta-catenin can promote these two disparate fates, with low levels fostering progenitor renewal and high levels driving differentiation. These results provide insight into how Wnt9b regulates distinct target genes that balance nephron progenitor renewal and differentiation.


Assuntos
Néfrons/fisiologia , beta Catenina/metabolismo , beta Catenina/fisiologia , Animais , Diferenciação Celular/genética , Regulação da Expressão Gênica/genética , Rim/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Néfrons/embriologia , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Células-Tronco/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologia
16.
Dokl Biol Sci ; 478(1): 22-25, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29536402

RESUMO

Ultrastructural study of the excretory tree of vestimentifera Ridgeia piscesae has shown that it consists of tubules that are blind at their distal ends. The tubules are lined with ciliated cells and have one or two multiciliated terminal cell(s) at the distal ends. In the tubule walls, there are putative ultrafiltration sites. The excretory tree tubules are interpreted as the secondary protonephridia.


Assuntos
Anelídeos/ultraestrutura , Animais , Anelídeos/fisiologia , Néfrons/fisiologia , Néfrons/ultraestrutura
17.
Pflugers Arch ; 470(2): 249-261, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28861607

RESUMO

Renin-angiotensin (RAS) and nitric oxide (NO) systems and the balance and interaction between them are considered of primary importance in maintaining fluid and electrolyte homeostasis. It has been suggested that the effects of NO may be modulated at least in part by the angiotensin (Ang) II, yet the roles of angiotensin receptor type 1 (AT1R) and type 2 (AT2R) are not well understood. Even though both Ang II and NO are elevated at birth and during the newborn period, their contribution to the adaptation of the newborn to life after birth as well as their physiological roles during development are poorly understood. The aim of this study was to determine if NO regulation of renal function during postnatal maturation is modulated by Ang II through activation of AT1R or AT2R or both receptors. Glomerular and tubular effects of either AT1R selective antagonist ZD 7155, AT2R selective antagonist PD 123319, and both antagonists ZD 7155 plus PD 123319, were measured in 1- (N = 9) and 6-week-old (N = 13) conscious, chronically instrumented lambs before and after removal of endogenous NO with L-arginine analogue, L-NAME. Two-way analysis of variance (ANOVA) procedures for repeated measures over time with factors age and treatment were used to compare the effects of the treatments on several glomerular and tubular variables in both groups. This study showed that L-NAME infusion after pre-treatment with ATR antagonists did not alter glomerular function in 1- or 6-week-old lambs. NO effects on electrolytes handling along the nephron during postnatal development were modulated by Ang II through AT1R and AT2R in an age-dependent manner. Selective inhibition of AT1R and AT2R increased excretion of Na+, K+, and Cl- in 6- but not in 1-week-old lambs. In 6-week-old lambs, urinary flow rate increased by 200%, free water clearance increased by 50%, and urine osmolality decreased by 40% after L-NAME was added to the pre-treatment with ZD 7155 plus PD 123319. When L-NAME was added either to ZD 7155 or PD 123319, the same trend in the alterations of these variables was observed, albeit to a lower degree. In conclusion, in conscious animals, during postnatal maturation, Ang II modulates the effects of NO on glomerular function, fluid, and electrolyte homeostasis through AT1Rs and AT2Rs in an age-dependent manner. Under physiological conditions, AT2Rs may potentiate the effects of AT1R, providing evidence of a crosstalk between ATRs in modulating NO effects on fluid and electrolyte homeostasis during postnatal maturation. This study provides new insights on the regulation of renal function during early postnatal development showing that, compared with later in life, newborns have impaired capacity to regulate glomerular function, water, and electrolyte balance.


Assuntos
Angiotensina II/metabolismo , Néfrons/metabolismo , Óxido Nítrico/metabolismo , Receptores de Angiotensina/metabolismo , Urodinâmica , Envelhecimento/fisiologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Feminino , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Néfrons/efeitos dos fármacos , Néfrons/crescimento & desenvolvimento , Néfrons/fisiologia , Ovinos , Vigília , Equilíbrio Hidroeletrolítico
18.
PLoS Genet ; 13(12): e1007093, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29240767

RESUMO

Congenital nephron number varies widely in the human population and individuals with low nephron number are at risk of developing hypertension and chronic kidney disease. The development of the kidney occurs via an orchestrated morphogenetic process where metanephric mesenchyme and ureteric bud reciprocally interact to induce nephron formation. The genetic networks that modulate the extent of this process and set the final nephron number are mostly unknown. Here, we identified a specific isoform of MITF (MITF-A), a bHLH-Zip transcription factor, as a novel regulator of the final nephron number. We showed that overexpression of MITF-A leads to a substantial increase of nephron number and bigger kidneys, whereas Mitfa deficiency results in reduced nephron number. Furthermore, we demonstrated that MITF-A triggers ureteric bud branching, a phenotype that is associated with increased ureteric bud cell proliferation. Molecular studies associated with an in silico analyses revealed that amongst the putative MITF-A targets, Ret was significantly modulated by MITF-A. Consistent with the key role of this network in kidney morphogenesis, Ret heterozygosis prevented the increase of nephron number in mice overexpressing MITF-A. Collectively, these results uncover a novel transcriptional network that controls branching morphogenesis during kidney development and identifies one of the first modifier genes of nephron endowment.


Assuntos
Rim/fisiologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Néfrons/fisiologia , Animais , Feminino , Humanos , Rim/embriologia , Rim/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fator de Transcrição Associado à Microftalmia/genética , Morfogênese , Néfrons/anatomia & histologia , Néfrons/crescimento & desenvolvimento , Néfrons/metabolismo , Organogênese , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ureter/metabolismo , Ureter/fisiologia
19.
N Engl J Med ; 376(24): 2349-2357, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28614683

RESUMO

BACKGROUND: The glomerular filtration rate (GFR) assesses the function of all nephrons, and the single-nephron GFR assesses the function of individual nephrons. How the single-nephron GFR relates to demographic and clinical characteristics and kidney-biopsy findings in humans is unknown. METHODS: We identified 1388 living kidney donors at the Mayo Clinic and the Cleveland Clinic who underwent a computed tomographic (CT) scan of the kidney with the use of contrast material and an iothalamate-based measurement of the GFR during donor evaluation and who underwent a kidney biopsy at donation. The mean single-nephron GFR was calculated as the GFR divided by the number of nephrons (calculated as the cortical volume of both kidneys as assessed on CT times the biopsy-determined glomerular density). Demographic and clinical characteristics and biopsy findings were correlated with the single-nephron GFR. RESULTS: A total of 58% of the donors were women, and the mean (±SD) age of the donors was 44±12 years. The mean GFR was 115±24 ml per minute, the mean number of nephrons was 860,000±370,000 per kidney, and the mean single-nephron GFR was 80±40 nl per minute. The single-nephron GFR did not vary significantly according to age (among donors <70 years of age), sex, or height (among donors ≤190 cm tall). A higher single-nephron GFR was independently associated with larger nephrons on biopsy and more glomerulosclerosis and arteriosclerosis than would be expected for age. A higher single-nephron GFR was associated with a height of more than 190 cm, obesity, and a family history of end-stage renal disease. CONCLUSIONS: Among healthy adult kidney donors, the single-nephron GFR was fairly constant with regard to age, sex, and height (if ≤190 cm). A higher single-nephron GFR was associated with certain risk factors for chronic kidney disease and certain kidney-biopsy findings. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).


Assuntos
Taxa de Filtração Glomerular , Transplante de Rim , Rim/patologia , Doadores Vivos , Néfrons/fisiologia , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Feminino , Humanos , Rim/anatomia & histologia , Rim/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nefroesclerose/patologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Tomografia Computadorizada por Raios X , Adulto Jovem
20.
J Vis Exp ; (124)2017 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-28605371

RESUMO

Acute Kidney Injury (AKI) is a common medical condition with a high mortality rate. With the repair abilities of the kidney, it is possible to restore adequate kidney function after supportive treatment. However, a better understanding of how nephron cell death and repair occur on the cellular level is required to minimize cell death and to enhance the regenerative process. The zebrafish pronephros is a good model system to accomplish this goal because it contains anatomical segments that are similar to the mammalian nephron. Previously, the most common model used to study kidney injury in fish was the pharmacological gentamicin model. However, this model does not allow for precise spatiotemporal control of injury, and hence it is difficult to study cellular and molecular processes involved in kidney repair. To overcome this limitation, this work presents a method through which, in contrast to the gentamicin approach, a specific Green Fuorescent Protein (GFP)-expressing nephron segment can be photoablated using a violet laser light (405 nm). This novel model of AKI provides many advantages that other methods of epithelial injury lack. Its main advantages are the ability to "dial" the level of injury and the precise spatiotemporal control in the robust in vivo animal model. This new method has the potential to significantly advance the level of understanding of kidney injury and repair mechanisms.


Assuntos
Lesão Renal Aguda/etiologia , Modelos Animais de Doenças , Terapia a Laser , Animais , Proteínas de Fluorescência Verde/genética , Néfrons/fisiologia , Pronefro/metabolismo , Peixe-Zebra/embriologia
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