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Collective Epithelial Migration Drives Kidney Repair after Acute Injury  [PDF]
Aurélien Palmyre, Jeongeun Lee, Gennadiy Ryklin, Troy Camarata, Martin K. Selig, Anne-Laure Duchemin, Paul Nowak, M. Amin Arnaout, Iain A. Drummond, Aleksandr Vasilyev
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101304
Abstract: Acute kidney injury (AKI) is a common and significant medical problem. Despite the kidney’s remarkable regenerative capacity, the mortality rate for the AKI patients is high. Thus, there remains a need to better understand the cellular mechanisms of nephron repair in order to develop new strategies that would enhance the intrinsic ability of kidney tissue to regenerate. Here, using a novel, laser ablation-based, zebrafish model of AKI, we show that collective migration of kidney epithelial cells is a primary early response to acute injury. We also show that cell proliferation is a late response of regenerating kidney epithelia that follows cell migration during kidney repair. We propose a computational model that predicts this temporal relationship and suggests that cell stretch is a mechanical link between migration and proliferation, and present experimental evidence in support of this hypothesis. Overall, this study advances our understanding of kidney repair mechanisms by highlighting a primary role for collective cell migration, laying a foundation for new approaches to treatment of AKI.
The Regulation of Apoptosis in Kidney Development: Implications for Nephron Number and Pattern?  [PDF]
Jacqueline Ho
Frontiers in Pediatrics , 2014, DOI: 10.3389/fped.2014.00128
Abstract: Apoptosis is essential to remodel developing structures and eliminate superfluous cells in a controlled manner during normal development, and continues to be an important component of tissue remodeling and regeneration during an organism’s lifespan, or as a response to injury. This mini review will discuss recent studies that have provided insights into the roles of apoptosis in the determination of nephron number and pattern, during normal and abnormal kidney development. The regulation of congenital nephron endowment has implications for risk of chronic kidney disease in later life, whereas abnormalities in nephron pattern are associated with congenital anomalies of the kidney and urinary tract (the leading cause of renal disease in children). Tight regulation of apoptosis is required in normal renal morphogenesis, although many questions remain regarding the regulation of apoptosis by genetic, epigenetic, and environmental factors, in addition to the functional requirement of different components of the apoptotic pathway.
Mechanical Stretch and PI3K Signaling Link Cell Migration and Proliferation to Coordinate Epithelial Tubule Morphogenesis in the Zebrafish Pronephros  [PDF]
Aleksandr Vasilyev, Yan Liu, Nathan Hellman, Narendra Pathak, Iain A. Drummond
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039992
Abstract: Organ development leads to the emergence of organ function, which in turn can impact developmental processes. Here we show that fluid flow-induced collective epithelial migration during kidney nephron morphogenesis induces cell stretch that in turn signals epithelial proliferation. Increased cell proliferation was dependent on PI3K signaling. Inhibiting epithelial proliferation by blocking PI3K or CDK4/Cyclin D1 activity arrested cell migration prematurely and caused a marked overstretching of the distal nephron tubule. Computational modeling of the involved cell processes predicted major morphological and kinetic outcomes observed experimentally under a variety of conditions. Overall, our findings suggest that kidney development is a recursive process where emerging organ function “feeds back” to the developmental program to influence fundamental cellular events such as cell migration and proliferation, thus defining final organ morphology.
Altered Ureteric Branching Morphogenesis and Nephron Endowment in Offspring of Diabetic and Insulin-Treated Pregnancy  [PDF]
Stacey N. Hokke, James A. Armitage, Victor G. Puelles, Kieran M. Short, Lynelle Jones, Ian M. Smyth, John F. Bertram, Luise A. Cullen-McEwen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058243
Abstract: There is strong evidence from human and animal models that exposure to maternal hyperglycemia during in utero development can detrimentally affect fetal kidney development. Notwithstanding this knowledge, the precise effects of diabetic pregnancy on the key processes of kidney development are unclear due to a paucity of studies and limitations in previously used methodologies. The purpose of the present study was to elucidate the effects of hyperglycemia on ureteric branching morphogenesis and nephrogenesis using unbiased techniques. Diabetes was induced in pregnant C57Bl/6J mice using multiple doses of streptozotocin (STZ) on embryonic days (E) 6.5-8.5. Branching morphogenesis was quantified ex vivo using Optical Projection Tomography, and nephrons were counted using unbiased stereology. Maternal hyperglycemia was recognised from E12.5. At E14.5, offspring of diabetic mice demonstrated fetal growth restriction and a marked deficit in ureteric tip number (control 283.7±23.3 vs. STZ 153.2±24.6, mean±SEM, p<0.01) and ureteric tree length (control 33.1±2.6 mm vs. STZ 17.6±2.7 mm, p = 0.001) vs. controls. At E18.5, fetal growth restriction was still present in offspring of STZ dams and a deficit in nephron endowment was observed (control 1246.2±64.9 vs. STZ 822.4±74.0, p<0.001). Kidney malformations in the form of duplex ureter and hydroureter were a common observation (26%) in embryos of diabetic pregnancy compared with controls (0%). Maternal insulin treatment from E13.5 normalised maternal glycaemia but did not normalise fetal weight nor prevent the nephron deficit. The detrimental effect of hyperglycemia on ureteric branching morphogenesis and, in turn, nephron endowment in the growth-restricted fetus highlights the importance of glycemic control in early gestation and during the initial stages of renal development.
Quantitative analysis of the nephron during human fetal kidney development  [PDF]
Dakovi?-Bjelakovi? Marija Z.,Vlajkovi? Slobodan R.,?ukuranovi? Rade E.,Anti? Svetlana
Vojnosanitetski Pregled , 2005, DOI: 10.2298/vsp0504281d
Abstract: Background. The development of human kidney is a complex process. The number, shape, size, and distribution of nephrons as functional units in a kidney, provide some important information about the organization of the kidney. The aim of this study was to extend the knowledge of the developing human kidney by studying nephrons in the kidney's cortex during gestation. Methods. Kidney tissue specimens of 32 human fetuses, the gestational age from IV lunar month (LM IV) to LM X, were analyzed. Specimens were divided in ten groups based on gestational age. Stereological methods were used at the light microscopic level to estimate the volume densities of the corpuscular and tubular components of the nephron in the cortex of the developing human kidney. Results. Nephron polymorphism was the main characteristic of the human fetal kidney during development. In younger fetuses, just below the renal capsule, there was a wide nephrogenic zone. It contained the condensed mesenchyme and terminal ends of the ureteric bud. Nephrons, in the different stages of development, were located around the ureteric bud which branched in the cortical nephrogenic zone and induced nephrogenesis. More mature nephrons were located in the deeper part of the cortex, close to the juxta-medullary junction. During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Glomeruli changed their size and shape, while the tubules changed their length and convolution. Renal cortex became wider and contained the more mature glomeruli and the more convoluted tubules. The volume density of the tubular component of the nephron increased continually from 10.53% (LM IVa) to 27.7% (LM X). Renal corpuscles changed their volume density irregularly during gestation, increasing from 13% (LM IVa) to 15.5% (LM IVb). During the increase of gestational age, the volume density of corpuscular component of the nephron decreased to 11.7% (LM VIII), then went on increasing until the end of the intrauterine development (LM X) when corpuscles occupied 16.73% of the cortical volume. The volume density of the developing nephrons (corpuscular and tubular portion) showed the significant positive correlation (r = 0.85; p<0.01) with gestational age. Conclusion. The present study was one of few quantitative studies of the human developing nephron. Knowledge about the normal development of the human kidney should be important for the future medical practice.
Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth  [PDF]
Mayumi Tomita, Misako Asada, Nariaki Asada, Jin Nakamura, Akiko Oguchi, Atsuko Y. Higashi, Shuichiro Endo, Elizabeth Robertson, Takeshi Kimura, Toru Kita, Aris N. Economides, Jordan Kreidberg, Motoko Yanagita
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073554
Abstract: The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth.
Collective Phenomena in Kidney Autoregulation
E. Mosekilde,O. V. Sosnovtseva,N.-H. Holstein-Rathlou
Transplantationsmedizin , 2005,
Abstract: By controlling the excretion of water and salts, the kidneys play an important role in regulating the blood pressure and maintaining a proper environment for the cells of the body. This control depends to a large extent on mechanisms that are associated with the individual functional unit, the nephron. However, a variety of cooperative phenomena arising through interactions between the nephrons may also be important. We present experimental evidence for a coupling between nephrons that are connected via a common piece of afferent arteriole. We also develop a mathematical model that can account for the observed synchronization phenomena, and discuss the possible physiological significance of these phenomena. We are particularly interested in synchronization effects that can occur among neighboring nephrons that individually display irregular (or chaotic) dynamics in their pressure and flow regulation.
A finite-volume scheme for a kidney nephron model  [cached]
Edwards Aurélie,Seguin Nicolas,Tournus Magali
ESAIM : Proceedings , 2012, DOI: 10.1051/proc/201235029
Abstract: We present a finite volume type scheme to solve a transport nephron model. The model consists in a system of transport equations with specific boundary conditions. The transport velocity is driven by another equation that can undergo sign changes during the transient regime. This is the main difficulty for the numerical resolution. The scheme we propose is based on an explicit resolution and is stable under a CFL condition which does not depend on the stiffness of source terms. Nous présentons un schéma numérique de type volume fini que l’on applique à un modèle de transport dans le néphron. Ce modèle consiste en un système d’équations de transport, avec des conditions aux bords spécifiques. La vitesse du transport est la solution d’un autre système d’équation et peut changer de signe au cours du régime transitoire. Ceci constitue la principale difficulté pour la résolution numérique. Le schéma proposé, basé sur une résolution explicite, est stable sous une condition CFL non restrictive.
Dynamic Image-Based Modelling of Kidney Branching Morphogenesis  [PDF]
Srivathsan Adivarahan,Denis Menshykau,Odysse Michos,Dagmar Iber
Quantitative Biology , 2013,
Abstract: Kidney branching morphogenesis has been studied extensively, but the mechanism that defines the branch points is still elusive. Here we obtained a 2D movie of kidney branching morphogenesis in culture to test different models of branching morphogenesis with physiological growth dynamics. We carried out image segmentation and calculated the displacement fields between the frames. The models were subsequently solved on the 2D domain, that was extracted from the movie. We find that Turing patterns are sensitive to the initial conditions when solved on the epithelial shapes. A previously proposed diffusion-dependent geometry effect allowed us to reproduce the growth fields reasonably well, both for an inhibitor of branching that was produced in the epithelium, and for an inducer of branching that was produced in the mesenchyme. The latter could be represented by Glial-derived neurotrophic factor (GDNF), which is expressed in the mesenchyme and induces outgrowth of ureteric branches. Considering that the Turing model represents the interaction between the GDNF and its receptor RET very well and that the model reproduces the relevant expression patterns in developing wildtype and mutant kidneys, it is well possible that a combination of the Turing mechanism and the geometry effect control branching morphogenesis.
Predicting the outcome of chronic kidney disease by the estimated nephron number: The rationale and design of PRONEP, a prospective, multicenter, observational cohort study
Toshiyuki Imasawa, Takashi Nakazato, Hiroo Ikehira, Hiroyuki Fujikawa, Ryo Nakajima, Takahito Ito, Yutaka Ando, Mitsuhiro Yoshimura, Masaru Nakayama, Kensei Yahata, Osamu Sasaki, Takaaki Yaomura, Ritsuko Katafuchi, Tsuyoshi Yamamura, Takehiko Kawaguchi, Motonobu Nishimura, Hiroshi Kitamura, Takashi Kenmochi, Akira Shimatsu
BMC Nephrology , 2012, DOI: 10.1186/1471-2369-13-11
Abstract: The hypothesis of this study is that the estimated nephron number can predict the outcome of a CKD patient. This will be a multicenter, prospective (minimum 3 and maximum 5 years follow-up) study. The subjects will comprise CKD patients aged over 14 years who have undergone a kidney biopsy. From January 2011 to March 2013, we will recruit 600 CKD patients from 10 hospitals belonging to the National Hospital Organization of Japan. The primary parameter for assessment is the composite of total mortality, renal death, cerebro-cardiovascular events, and a 50% reduction in the eGFR. The secondary parameter is the rate of eGFR decline per year. The nephron number will be estimated by the glomerular density in biopsy specimens and the renal cortex volume. This study includes one sub-cohort study to establish the equation to calculate the renal cortex volume. Enrollment will be performed at the time of the kidney biopsy, and the data will consist of a medical interview, ultrasound for measurement of the kidney size, blood or urine test, and the pathological findings of the kidney biopsy. Patients will continue to have medical consultations and receive examinations and/or treatment as usual. The data from the patients will be collected once a year after the kidney biopsy until March 2016. All data using this study are easily obtained in routine clinical practice.This study includes the first trials to estimate the renal cortex volume and nephron number in the general clinical setting. Furthermore, this is the first prospective study to examine whether the nephron number predicts the outcome of CKD patients. The results from this study should provide powerful new tools for nephrologists in routine clinical practice.UMIN-Clinical Trial Registration, UMIN000004784.Previous studies suggested that chronic kidney disease (CKD) is one of the most important risk factors for cardiovascular disease among known other risk factors, such as diabetes, hypertension, hyperlipidemia, obesity
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