scholarly journals Expression of ILK in renal stroma is essential for multiple aspects of renal development

2018 ◽  
Vol 315 (2) ◽  
pp. F374-F385
Author(s):  
Xiaohui Gong ◽  
Xiaoxia Guo ◽  
Ru Huang ◽  
Huimin Liao ◽  
Qingquan Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Kidney Development ◽  
Collecting Duct ◽  
Mesenchymal Cell ◽  
Branching Morphogenesis ◽  
Metanephric Mesenchyme ◽  
Vascular Differentiation ◽  
Renal Vasculature ◽  
Developmental Defects

Kidney development involves reciprocal and inductive interactions between the ureteric bud (UB) and surrounding metanephric mesenchyme. Signals from renal stromal lineages are essential for differentiation and patterning of renal epithelial and mesenchymal cell types and renal vasculogenesis; however, underlying mechanisms remain not fully understood. Integrin-linked kinase (ILK), a key component of integrin signaling pathway, plays an important role in kidney development. However, the role of ILK in renal stroma remains unknown. Here, we ablated ILK in renal stromal lineages using a platelet-derived growth factor receptor B ( Pdgfrb) -Cre mouse line, and the resulting Ilk mutant mice presented postnatal growth retardation and died within 3 wk of age with severe renal developmental defects. Pdgfrb-Cre;Ilk mutant kidneys exhibited a significant decrease in UB branching and disrupted collecting duct formation. From E16.5 onward, renal interstitium was disorganized, forming medullary interstitial pseudocysts. Pdgfrb-Cre;Ilk mutants exhibited renal vasculature mispatterning and impaired glomerular vascular differentiation. Impaired glial cell-derived neurotrophic factor/Ret and bone morphogenetic protein 7 signaling pathways were observed in Pdgfrb-Cre;Ilk mutant kidneys. Furthermore, phosphoproteomic and Western blot analyses revealed a significant dysregulation of a number of key signaling pathways required for kidney morphogenesis, including PI3K/AKT and MAPK/ERK in Pdgfrb-Cre;Ilk mutants. Our results revealed a critical requirement for ILK in renal-stromal and vascular development, as well as a noncell autonomous role of ILK in UB branching morphogenesis.

scholarly journals Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt

2015 ◽  
Vol 26 (10) ◽  
pp. 1857-1874 ◽  
Author(s):  
Eugenia M. Yazlovitskaya ◽  
Hui-Yuan Tseng ◽  
Olga Viquez ◽  
Tianxiang Tu ◽  
Glenda Mernaugh ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Collecting Duct ◽  
Duct Cell ◽  
Branching Morphogenesis ◽  
Null Mouse ◽  
Developmental Defects ◽  
Akt Activation ◽  
Cell Functions ◽  
Integrin Α3β1 ◽  
Collecting System

The collecting system of the kidney develops from the ureteric bud (UB), which undergoes branching morphogenesis, a process regulated by multiple factors, including integrin–extracellular matrix interactions. The laminin (LM)-binding integrin α3β1 is crucial for this developmental program; however, the LM types and LM/integrin α3β1–dependent signaling pathways are poorly defined. We show that α3 chain–containing LMs promote normal UB branching morphogenesis and that LM-332 is a better substrate than LM-511 for stimulating integrin α3β1–dependent collecting duct cell functions. We demonstrate that integrin α3β1–mediated cell adhesion to LM-332 modulates Akt activation in the developing collecting system and that Akt activation is PI3K independent but requires decreased PTEN activity and K63-linked polyubiquitination. We identified the ubiquitin-modifying enzyme TRAF6 as an interactor with the integrin β1 subunit and regulator of integrin α3β1–dependent Akt activation. Finally, we established that the developmental defects of TRAF6- and integrin α3–null mouse kidneys are similar. Thus K63-linked polyubiquitination plays a previously unrecognized role in integrin α3β1–dependent cell signaling required for UB development and may represent a novel mechanism whereby integrins regulate signaling pathways.

Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips

Development ◽  
1996 ◽  
Vol 122 (11) ◽  
pp. 3627-3637 ◽  
Author(s):  
A. Kispert ◽  
S. Vainio ◽  
L. Shen ◽  
D.H. Rowitch ◽  
A.P. McMahon
Keyword(s):  
Collecting Duct ◽  
Expression Patterns ◽  
Branching Morphogenesis ◽  
Proteoglycan Synthesis ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Metanephric Kidney ◽  
Specific Factors ◽  
Collecting Duct Epithelium ◽  
Metanephric Blastema

Development of the metanephric kidney requires the concerted interaction of two tissues, the epithelium of the ureteric duct and the metanephric mesenchyme. Signals from the ureter induce the metanephric mesenchyme to condense and proliferate around the ureter tip, reciprocal signals from the mesenchyme induce the ureter tip to grow and to branch. Wnt genes encode secreted glycoproteins, which are candidate mediators of these signaling events. We have identified three Wnt genes with specific, non-overlapping expression patterns in the metanephric kidney, Wnt-4, Wnt-7b and Wnt-11. Wnt-4 is expressed in the condensing mesenchyme and the comma- and S-shaped bodies. Wnt-7b is expressed in the collecting duct epithelium from 13.5 days post coitum onward. Wnt-1l is first expressed in the nephric duct adjacent to the metanephric blastema prior to the outgrowth of the ureteric bud. Wnt-l1 expression in Danforth's short-tail mice suggests that signaling from the mesenchyme may regulate Wnt-ll activation. During metanephric development, Wnt-11 expression is confined to the tips of the branching ureter. Maintenance of this expression is independent of Wnt-4 signaling and mature mesenchymal elements in the kidney. Moreover, Wnt-ll expression is maintained in recombinants between ureter and lung mesenchyme suggesting that branching morphogenesis and maintenance of Wnt-ll expression are independent of metanephric mesenchyme-specific factors. Interference with proteoglycan synthesis leads to loss of Wnt-ll expression in the ureter tip. We suggest that Wnt-11 acts as an autocrine factor within the ureter epithelium and that its expression is regulated at least in part by proteoglycans.

Prorenin receptor controls renal branching morphogenesis via Wnt/β-catenin signaling

2017 ◽  
Vol 312 (3) ◽  
pp. F407-F417 ◽  
Author(s):  
Renfang Song ◽  
Adam Janssen ◽  
Yuwen Li ◽  
Samir El-Dahr ◽  
Ihor V. Yosypiv
Keyword(s):  
Kidney Development ◽  
Collecting Duct ◽  
Terminal Differentiation ◽  
Molecular Transport ◽  
Branching Morphogenesis ◽  
Primary Role ◽  
Prorenin Receptor ◽  
Accessory Subunit

The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H+-ATPase. Renal branching morphogenesis, defined as growth and branching of the ureteric bud (UB), is essential for mammalian kidney development. Previously, we demonstrated that conditional ablation of the PRR in the UB in PRRUB−/− mice causes severe defects in UB branching, resulting in marked kidney hypoplasia at birth. Here, we investigated the UB transcriptome using whole genome-based analysis of gene expression in UB cells, FACS-isolated from PRRUB−/−, and control kidneys at birth (P0) to determine the primary role of the PRR in terminal differentiation and growth of UB-derived collecting ducts. Three genes with expression in UB cells that previously shown to regulate UB branching morphogenesis, including Wnt9b, β-catenin, and Fgfr2, were upregulated, whereas the expression of Wnt11, Bmp7, Etv4, and Gfrα1 was downregulated. We next demonstrated that infection of immortalized UB cells with shPRR in vitro or deletion of the UB PRR in double-transgenic PRRUB−/−/ BatGal+ mice, a reporter strain for β-catenin transcriptional activity, in vivo increases β-catenin activity in the UB epithelia. In addition to UB morphogenetic genes, the functional groups of differentially expressed genes within the downregulated gene set included genes involved in molecular transport, metabolic disease, amino acid metabolism, and energy production. Together, these data demonstrate that UB PRR performs essential functions during UB branching and collecting duct morphogenesis via control of a hierarchy of genes that control UB branching and terminal differentiation of the collecting duct cells.

scholarly journals Organ-Specific Branching Morphogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Christine Lang ◽  
Lisa Conrad ◽  
Dagmar Iber
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Developmental Disorders ◽  
Developmental Process ◽  
Branching Morphogenesis ◽  
Epithelial Morphogenesis ◽  
Organ Specific ◽  
Different Shapes ◽  
Organ Shape

A common developmental process, called branching morphogenesis, generates the epithelial trees in a variety of organs, including the lungs, kidneys, and glands. How branching morphogenesis can create epithelial architectures of very different shapes and functions remains elusive. In this review, we compare branching morphogenesis and its regulation in lungs and kidneys and discuss the role of signaling pathways, the mesenchyme, the extracellular matrix, and the cytoskeleton as potential organ-specific determinants of branch position, orientation, and shape. Identifying the determinants of branch and organ shape and their adaptation in different organs may reveal how a highly conserved developmental process can be adapted to different structural and functional frameworks and should provide important insights into epithelial morphogenesis and developmental disorders.

Stromal cells mediate retinoid-dependent functions essential for renal development

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
C. Mendelsohn ◽  
E. Batourina ◽  
S. Fung ◽  
T. Gilbert ◽  
J. Dodd
Keyword(s):  
Vitamin A ◽  
Stromal Cells ◽  
Renal Cell ◽  
Kidney Development ◽  
Collecting Duct ◽  
Cell Types ◽  
Renal Development ◽  
Ureteric Bud ◽  
Renal Malformations

The essential role of vitamin A and its metabolites, retinoids, in kidney development has been demonstrated in vitamin A deficiency and gene targeting studies. Retinoids signal via nuclear transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families. Inactivation of RARaplpha and RARbeta2 receptors together, but not singly, resulted in renal malformations, suggesting that within a given renal cell type, their concerted function is required for renal morphogenesis. At birth, RARalpha beta2(−) mutants displayed small kidneys, containing few ureteric bud branches, reduced numbers of nephrons and lacking the nephrogenic zone where new nephrons are continuously added. These observations have prompted us to investigate the role of RARalpha and RARbeta2 in renal development in detail. We have found that within the embryonic kidney, RARalpha and RARbeta2 are colocalized in stromal cells, but not in other renal cell types, suggesting that stromal cells mediate retinoid-dependent functions essential for renal development. Analysis of RARalpha beta2(−) mutant kidneys at embryonic stages revealed that nephrons were formed and revealed no changes in the intensity or distribution of molecular markers specific for different metanephric mesenchymal cell types. In contrast the development of the collecting duct system was greatly impaired in RARalpha beta2(−) mutant kidneys. Fewer ureteric bud branches were present, and ureteric bud ends were positioned abnormally, at a distance from the renal capsule. Analysis of genes important for ureteric bud morphogenesis revealed that the proto-oncogene c-ret was downregulated. Our results suggest that RARalpha and RARbeta2 are required for generating stromal cell signals that maintain c-ret expression in the embryonic kidney. Since c-ret signaling is required for ureteric bud morphogenesis, loss of c-ret expression is a likely cause of impaired ureteric bud branching in RARalpha beta2(−) mutants.

scholarly journals β1-Integrin is required for kidney collecting duct morphogenesis and maintenance of renal function

2009 ◽  
Vol 297 (1) ◽  
pp. F210-F217 ◽  
Author(s):  
Wei Wu ◽  
Shinji Kitamura ◽  
David M. Truong ◽  
Timo Rieg ◽  
Volker Vallon ◽  
...  
Keyword(s):  
Renal Agenesis ◽  
Collecting Duct ◽  
Cyst Formation ◽  
Branching Morphogenesis ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Collecting Ducts ◽  
Medullary Collecting Duct ◽  
Apparent Ability ◽  
Collecting System

Deletion of integrin-β1 ( Itgb1) in the kidney collecting system led to progressive renal dysfunction and polyuria. The defect in the concentrating ability of the kidney was concomitant with decreased medullary collecting duct expression of aquaporin-2 and arginine vasopressin receptor 2, while histological examination revealed hypoplastic renal medullary collecting ducts characterized by increased apoptosis, ectasia and cyst formation. In addition, a range of defects from small kidneys with cysts and dilated tubules to bilateral renal agenesis was observed. This was likely due to altered growth and branching morphogenesis of the ureteric bud (the progenitor tissue of the renal collecting system), despite the apparent ability of the ureteric bud-derived cells to induce differentiation of the metanephric mesenchyme. These data not only support a role for Itgb1 in the development of the renal collecting system but also raise the possibility that Itgb1 links morphogenesis to terminal differentiation and ultimately collecting duct function and/or maintenance.

scholarly journals Kidney Organoids and Tubuloids

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1326 ◽  
Author(s):  
Fjodor A. Yousef Yengej ◽  
Jitske Jansen ◽  
Maarten B. Rookmaaker ◽  
Marianne C. Verhaar ◽  
Hans Clevers
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Kidney Development ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Metanephric Mesenchyme ◽  
Kidney Organoids

In the past five years, pluripotent stem cell (PSC)-derived kidney organoids and adult stem or progenitor cell (ASC)-based kidney tubuloids have emerged as advanced in vitro models of kidney development, physiology, and disease. PSC-derived organoids mimic nephrogenesis. After differentiation towards the kidney precursor tissues ureteric bud and metanephric mesenchyme, their reciprocal interaction causes self-organization and patterning in vitro to generate nephron structures that resemble the fetal kidney. ASC tubuloids on the other hand recapitulate renewal and repair in the adult kidney tubule and give rise to long-term expandable and genetically stable cultures that consist of adult proximal tubule, loop of Henle, distal tubule, and collecting duct epithelium. Both organoid types hold great potential for: (1) studies of kidney physiology, (2) disease modeling, (3) high-throughput screening for drug efficacy and toxicity, and (4) regenerative medicine. Currently, organoids and tubuloids are successfully used to model hereditary, infectious, toxic, metabolic, and malignant kidney diseases and to screen for effective therapies. Furthermore, a tumor tubuloid biobank was established, which allows studies of pathogenic mutations and novel drug targets in a large group of patients. In this review, we discuss the nature of kidney organoids and tubuloids and their current and future applications in science and medicine.

scholarly journals Generation of kidney ureteric bud and collecting duct organoids that recapitulate kidney branching morphogenesis

2020 ◽  
Author(s):  
Zipeng Zeng ◽  
Biao Huang ◽  
Riana K. Parvez ◽  
Yidan Li ◽  
Jyunhao Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Kidney Development ◽  
De Novo ◽  
Collecting Duct ◽  
Branching Morphogenesis ◽  
Ureteric Bud ◽  
Primary Mouse ◽  
Collecting System

AbstractKidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from pluripotent human stem cells. UB organoids differentiate into CD organoids in vitro, with differentiated cell types adopting spatial assemblies reflective of the adult kidney collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Combining efficient gene editing with the UB organoid model will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting system.One sentence summaryCollecting duct organoids derived from primary mouse and human ureteric bud progenitor cells and human pluripotent stem cells provide an in vitro platform for genetic dissection of development, regeneration and diseases of the mammalian collecting system.

scholarly journals Hoxa11andHoxd11regulate branching morphogenesis of the ureteric bud in the developing kidney

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 2153-2161 ◽  
Author(s):  
Larry T. Patterson ◽  
Martina Pembaur ◽  
S. Steven Potter
Keyword(s):  
Gene Expression ◽  
Kidney Development ◽  
Growth Failure ◽  
Immunohistochemical Analysis ◽  
Branching Morphogenesis ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Metanephric Kidney ◽  
Normal Gene ◽  
Ureteric Buds

Hoxa11 and Hoxd11 are functionally redundant during kidney development. Mice with homozygous null mutation of either gene have normal kidneys, but double mutants have rudimentary, or in extreme cases, absent kidneys. We have examined the mechanism for renal growth failure in this mouse model and find defects in ureteric bud branching morphogenesis. The ureteric buds are either unbranched or have an atypical pattern characterized by lack of terminal branches in the midventral renal cortex. The mutant embryos show that Hoxa11 and Hoxd11 control development of a dorsoventral renal axis. By immunohistochemical analysis, Hoxa11 expression is restricted to the early metanephric mesenchyme, which induces ureteric bud formation and branching. It is not found in the ureteric bud. This suggests that the branching defect had been caused by failure of mesenchyme to epithelium signaling. In situ hybridizations with Wnt7b, a marker of the metanephric kidney, show that the branching defect was not simply the result of homeotic transformation of metanephros to mesonephros. Absent Bf2 and Gdnf expression in the midventral mesenchyme, findings that could by themselves account for branching defects, shows that Hoxa11 and Hoxd11 are necessary for normal gene expression in the ventral mesenchyme. Attenuation of normal gene expression along with the absence of a detectable proliferative or apoptotic change in the mutants show that one function of Hoxa11 and Hoxd11 in the developing renal mesenchyme is to regulate differentiation necessary for mesenchymal-epithelial reciprocal inductive interactions.

scholarly journals Unravelling the Role of PAX2 Mutation in Human Focal Segmental Glomerulosclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1808
Author(s):  
Lorena Longaretti ◽  
Piera Trionfini ◽  
Valerio Brizi ◽  
Christodoulos Xinaris ◽  
Caterina Mele ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Cell Injury ◽  
Normal Structure ◽  
Branching Morphogenesis ◽  
Patient Specific ◽  
Developmental Defects ◽  
Segmental Glomerulosclerosis

No effective treatments are available for familial steroid-resistant Focal Segmental Glomerulosclerosis (FSGS), characterized by proteinuria due to ultrastructural abnormalities in glomerular podocytes. Here, we studied a private PAX2 mutation identified in a patient who developed FSGS in adulthood. By generating adult podocytes using patient-specific induced pluripotent stem cells (iPSC), we developed an in vitro model to dissect the role of this mutation in the onset of FSGS. Despite the PAX2 mutation, patient iPSC properly differentiated into podocytes that exhibited a normal structure and function when compared to control podocytes. However, when exposed to an environmental trigger, patient podocytes were less viable and more susceptible to cell injury. Fixing the mutation improved their phenotype and functionality. Using a branching morphogenesis assay, we documented developmental defects in patient-derived ureteric bud-like tubules that were totally rescued by fixing the mutation. These data strongly support the hypothesis that the PAX2 mutation has a dual effect, first in renal organogenesis, which could account for a suboptimal nephron number at birth, and second in adult podocytes, which are more susceptible to cell death caused by environmental triggers. These abnormalities might translate into the development of proteinuria in vivo, with a progressive decline in renal function, leading to FSGS.

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