scholarly journals Stromal prorenin receptor is critical for normal kidney development

2019 ◽  
Vol 316 (5) ◽  
pp. R640-R650 ◽  
Author(s):  
Ihor V. Yosypiv ◽  
Maria Luisa S. Sequeira-Lopez ◽  
Renfang Song ◽  
Alexandre De Goes Martini
Keyword(s):  
Kidney Development ◽  
Marked Decrease ◽  
Specific Marker ◽  
Normal Kidney ◽  
Arterial Tree ◽  
Conditional Deletion ◽  
Nephron Progenitors ◽  
Prorenin Receptor ◽  
Accessory Subunit ◽  
Metanephric Kidney

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.

scholarly journals Von Hippel-Lindau Acts as a Metabolic Switch Controlling Nephron Progenitor Differentiation

2019 ◽  
Vol 30 (7) ◽  
pp. 1192-1205 ◽  
Author(s):  
Kasey Cargill ◽  
Shelby L. Hemker ◽  
Andrew Clugston ◽  
Anjana Murali ◽  
Elina Mukherjee ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Metabolic Regulation ◽  
Kidney Development ◽  
Developmentally Delayed ◽  
Metabolic Switch ◽  
Von Hippel Lindau ◽  
Conditional Deletion ◽  
Nephron Progenitors ◽  
Ubiquitin Ligase Complex ◽  
Nephron Progenitor

BackgroundNephron progenitors, the cell population that give rise to the functional unit of the kidney, are metabolically active and self-renew under glycolytic conditions. A switch from glycolysis to mitochondrial respiration drives these cells toward differentiation, but the mechanisms that control this switch are poorly defined. Studies have demonstrated that kidney formation is highly dependent on oxygen concentration, which is largely regulated by von Hippel-Lindau (VHL; a protein component of a ubiquitin ligase complex) and hypoxia-inducible factors (a family of transcription factors activated by hypoxia).MethodsTo explore VHL as a regulator defining nephron progenitor self-renewal versus differentiation, we bred Six2-TGCtg mice with VHLlox/lox mice to generate mice with a conditional deletion of VHL from Six2+ nephron progenitors. We used histologic, immunofluorescence, RNA sequencing, and metabolic assays to characterize kidneys from these mice and controls during development and up to postnatal day 21.ResultsBy embryonic day 15.5, kidneys of nephron progenitor cell–specific VHL knockout mice begin to exhibit reduced maturation of nephron progenitors. Compared with controls, VHL knockout kidneys are smaller and developmentally delayed by postnatal day 1, and have about half the number of glomeruli at postnatal day 21. VHL knockout nephron progenitors also exhibit persistent Six2 and Wt1 expression, as well as decreased mitochondrial respiration and prolonged reliance on glycolysis.ConclusionsOur findings identify a novel role for VHL in mediating nephron progenitor differentiation through metabolic regulation, and suggest that VHL is required for normal kidney development.

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.

Growth factors and metanephrogenesis

1992 ◽  
Vol 262 (4) ◽  
pp. F523-F532 ◽  
Author(s):  
M. R. Hammerman ◽  
S. A. Rogers ◽  
G. Ryan
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Kidney Development ◽  
Transforming Growth Factor ◽  
Polypeptide Growth Factors ◽  
Metanephric Kidney ◽  
Epidermal Growth ◽  
Factor Alpha ◽  
Editorial Review

The formation of all organs during embryogenesis, including kidney, is dependent on the timed and sequential expression of a number of polypeptide growth factors. Synthesis and actions of one or more members of the insulin-like growth factor, epidermal growth factor/transforming growth factor-alpha, transforming growth factor-beta, platelet-derived growth factor, fibroblast growth factor, and nerve growth factor families have been characterized in the developing metanephric kidney. Studies originating from a number of laboratories have defined the localization of growth factor mRNAs, receptors and peptides, have delineated patterns of growth factor synthesis, and have established the growth factor dependency of embryonic kidney development. The results of these investigations will be summarized in this editorial review and integrated within the broader context of growth factor cellular physiology and growth factor expression in nonrenal systems.

scholarly journals Single-cell RNA sequencing reveals differential cell cycle activity in key cell populations during nephrogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abha S. Bais ◽  
Débora M. Cerqueira ◽  
Andrew Clugston ◽  
Andrew J. Bodnar ◽  
Jacqueline Ho ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Collecting Duct ◽  
Cell Types ◽  
Nephron Progenitors ◽  
Developing Kidney ◽  
Distal Tubules ◽  
Cycle Regulation

AbstractThe kidney is a complex organ composed of more than 30 terminally differentiated cell types that all are required to perform its numerous homeostatic functions. Defects in kidney development are a significant cause of chronic kidney disease in children, which can lead to kidney failure that can only be treated by transplant or dialysis. A better understanding of molecular mechanisms that drive kidney development is important for designing strategies to enhance renal repair and regeneration. In this study, we profiled gene expression in the developing mouse kidney at embryonic day 14.5 at single-cell resolution. Consistent with previous studies, clusters with distinct transcriptional signatures clearly identify major compartments and cell types of the developing kidney. Cell cycle activity distinguishes between the “primed” and “self-renewing” sub-populations of nephron progenitors, with increased expression of the cell cycle-related genes Birc5, Cdca3, Smc2 and Smc4 in “primed” nephron progenitors. In addition, augmented expression of cell cycle related genes Birc5, Cks2, Ccnb1, Ccnd1 and Tuba1a/b was detected in immature distal tubules, suggesting cell cycle regulation may be required for early events of nephron patterning and tubular fusion between the distal nephron and collecting duct epithelia.

scholarly journals Arl13b and the exocyst interact synergistically in ciliogenesis

2016 ◽  
Vol 27 (2) ◽  
pp. 308-320 ◽  
Author(s):  
Cecília Seixas ◽  
Soo Young Choi ◽  
Noemi Polgar ◽  
Nicole L. Umberger ◽  
Michael P. East ◽  
...  
Keyword(s):  
Kidney Development ◽  
Genetic Interaction ◽  
Joubert Syndrome ◽  
Conditional Knockout ◽  
Multiple Organs ◽  
Conditional Deletion ◽  
Curly Tail ◽  
Adp Ribosylation Factor ◽  
Precise Role

Arl13b belongs to the ADP-ribosylation factor family within the Ras superfamily of regulatory GTPases. Mutations in Arl13b cause Joubert syndrome, which is characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. Arl13b is highly enriched in cilia and is required for ciliogenesis in multiple organs. Nevertheless, the precise role of Arl13b remains elusive. Here we report that the exocyst subunits Sec8, Exo70, and Sec5 bind preferentially to the GTP-bound form of Arl13b, consistent with the exocyst being an effector of Arl13b. Moreover, we show that Arl13b binds directly to Sec8 and Sec5. In zebrafish, depletion of arl13b or the exocyst subunit sec10 causes phenotypes characteristic of defective cilia, such as curly tail up, edema, and abnormal pronephric kidney development. We explored this further and found a synergistic genetic interaction between arl13b and sec10 morphants in cilia-dependent phenotypes. Through conditional deletion of Arl13b or Sec10 in mice, we found kidney cysts and decreased ciliogenesis in cells surrounding the cysts. Moreover, we observed a decrease in Arl13b expression in the kidneys from Sec10 conditional knockout mice. Taken together, our results indicate that Arl13b and the exocyst function together in the same pathway leading to functional cilia.

scholarly journals Genetic Dissection of Cadherin Function during Nephrogenesis

2002 ◽  
Vol 22 (5) ◽  
pp. 1474-1487 ◽  
Author(s):  
Ulf Dahl ◽  
Anders Sjödin ◽  
Lionel Larue ◽  
Glenn L. Radice ◽  
Stefan Cajander ◽  
...  
Keyword(s):  
Kidney Development ◽  
Morphological Changes ◽  
Genetic Dissection ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Metanephric Kidney ◽  
The Individual ◽  
Deficient Mice

ABSTRACT The distinct expression of R-cadherin in the induced aggregating metanephric mesenchyme suggests that it may regulate the mesenchymal-epithelial transition during kidney development. To address whether R-cadherin is required for kidney ontogeny, R-cadherin-deficient mice were generated. These mice appeared to be healthy and were fertile, demonstrating that R-cadherin is not essential for embryogenesis. The only kidney phenotype of adult mutant animals was the appearance of dilated proximal tubules, which was associated with an accumulation of large intracellular vacuoles. Morphological analysis of nephrogenesis in R-cadherin −/− mice in vivo and in vitro revealed defects in the development of both ureteric bud-derived cells and metanephric mesenchyme-derived cells. First, the morphology and organization of the proximal parts of the ureteric bud epithelium were altered. Interestingly, these morphological changes correlated with an increased rate of apoptosis and were further supported by perturbed branching and patterning of the ureteric bud epithelium during in vitro differentiation. Second, during in vitro studies of mesenchymal-epithelial conversion, significantly fewer epithelial structures developed from R-cadherin −/− kidneys than from wild-type kidneys. These data suggest that R-cadherin is functionally involved in the differentiation of both mesenchymal and epithelial components during metanephric kidney development. Finally, to investigate whether the redundant expression of other classic cadherins expressed in the kidney could explain the rather mild kidney defects in R-cadherin-deficient mice, we intercrossed R-cadherin −/− mice with cadherin-6−/− , P-cadherin −/−, and N-cadherin +/− mice. Surprisingly, however, in none of the compound knockout strains was kidney development affected to a greater extent than within the individual cadherin knockout strains.

scholarly journals Prorenin receptor is critical for nephron progenitors

2016 ◽  
Vol 409 (2) ◽  
pp. 382-391 ◽  
Author(s):  
Renfang Song ◽  
Graeme Preston ◽  
Laura Kidd ◽  
Daniel Bushnell ◽  
Sunder Sims-Lucas ◽  
...  
Keyword(s):  
Nephron Progenitors ◽  
Prorenin Receptor

scholarly journals Kctd15 regulates nephron segment development by repressing Tfap2a activity

2020 ◽  
Author(s):  
Brooke E. Chambers ◽  
Eleanor G. Clark ◽  
Allison E. Gatz ◽  
Rebecca A. Wingert
Keyword(s):  
Transcription Factor ◽  
Kidney Development ◽  
Distal Tubule ◽  
Thick Ascending Limb ◽  
Nephron Progenitors ◽  
Nephron Segment ◽  
Feedback Module ◽  
Zebrafish Pronephros ◽  
First Time ◽  
Solute Transporters

AbstractA functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules that contain a sequence of segments each expressing a distinct repertoire of solute transporters. To date, the transcriptional codes driving regional specification, solute transporter program activation, and terminal differentiation of segment populations remain poorly understood. We demonstrate for the first time that the KCTD15 paralogs, kctd15a and kctd15b, function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors co-localized with tfap2a in distal tubule precursors. kctd15 loss primed nephron cells to adopt distal fates by driving expansions in slc12a1, kcnj1a.1, and stc1 marker expression. These phenotypes were resultant of Tfap2a hyperactivity, where kctd15a/b-deficient embryos exhibited increased abundance of this transcription factor. Interestingly, tfap2a reciprocally promoted kctd15 transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitant kctd15b knockdown with tfap2a overexpression produced genetic synergy and further expanded the DE population. Our study provides strong evidence that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.

scholarly journals Prorenin receptor and ERK are associated with kidney development in the fetal rat with prenatal glucocorticoid administration.

2019 ◽  
Vol 92 (0) ◽  
pp. 3-P-073
Author(s):  
Yuko Takeba ◽  
Makoto Yamamoto ◽  
Tsukasa Kobayashi ◽  
Atsuko Kamijyo-Ikemori ◽  
Masanori Ootaki ◽  
...  
Keyword(s):  
Kidney Development ◽  
Fetal Rat ◽  
Prorenin Receptor ◽  
Glucocorticoid Administration

scholarly journals β-catenin regulates the formation of multiple nephron segments in the mouse kidney

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Patrick Deacon ◽  
Charles W. Concodora ◽  
Eunah Chung ◽  
Joo-Seop Park
Keyword(s):  
Kidney Development ◽  
Critical Role ◽  
Mouse Kidney ◽  
Proximal Tubules ◽  
Stable Form ◽  
Loss Of Function ◽  
Nephron Segments ◽  
Mesenchymal To Epithelial Transition ◽  
Nephron Progenitors ◽  
Nephron Segmentation

Abstract The nephron is composed of distinct segments that perform unique physiological functions. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron segmentation after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Expression of a stable form of β-catenin in epithelial nephron progenitors blocked the proper formation of all nephron segments, suggesting tight regulation of β-catenin signaling during nephron segmentation. This work shows that β-catenin regulates the formation of multiple nephron segments along the proximo-distal axis of the mammalian nephron.

Sign in / Sign up

Export Citation Format

Share Document