scholarly journals Notch Signaling in Kidney Development, Maintenance, and Disease

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 692 ◽  
Author(s):  
Malini Mukherjee ◽  
Eric Fogarty ◽  
Madhusudhana Janga ◽  
Kameswaran Surendran
Keyword(s):  
Epithelial Cell ◽  
Notch Signaling ◽  
Kidney Development ◽  
Kidney Diseases ◽  
Human Kidney ◽  
Cell Types ◽  
Multiple Roles ◽  
Collecting Ducts ◽  
Kidney Epithelial Cell ◽  
Nephron Progenitor

Kidney development involves formation of nephrons intricately aligned with the vasculature and connected to a branched network of collecting ducts. Notch signaling plays multiple roles during kidney development involving the formation of nephrons composed of diverse epithelial cell types arranged into tubular segments, all the while maintaining a nephron progenitor niche. Here, we review the roles of Notch signaling identified from rodent kidney development and injury studies, while discussing human kidney diseases associated with aberrant Notch signaling. We also review Notch signaling requirement in maintenance of mature kidney epithelial cell states and speculate that Notch activity regulation mediates certain renal physiologic adaptations.

scholarly journals Endogenous Notch Signaling in Adult Kidneys Maintains Segment-Specific Epithelial Cell Types of the Distal Tubules and Collecting Ducts to Ensure Water Homeostasis

2018 ◽  
Vol 30 (1) ◽  
pp. 110-126 ◽  
Author(s):  
Malini Mukherjee ◽  
Jennifer deRiso ◽  
Karla Otterpohl ◽  
Ishara Ratnayake ◽  
Divya Kota ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Notch Signaling ◽  
Kidney Development ◽  
Collecting Duct ◽  
Lithium Treatment ◽  
Cell Types ◽  
Intercalated Cells ◽  
Principal Cells ◽  
Adult Kidney ◽  
Collecting Ducts

BackgroundNotch signaling is required during kidney development for nephron formation and principal cell fate selection within the collecting ducts. Whether Notch signaling is required in the adult kidney to maintain epithelial diversity, or whether its loss can trigger principal cell transdifferentiation (which could explain acquired diabetes insipidus in patients receiving lithium) is unclear.MethodsTo investigate whether loss of Notch signaling can trigger principal cells to lose their identity, we genetically inactivated Notch1 and Notch2, inactivated the Notch signaling target Hes1, or induced expression of a Notch signaling inhibitor in all of the nephron segments and collecting ducts in mice after kidney development. We examined renal function and cell type composition of control littermates and mice with conditional Notch signaling inactivation in adult renal epithelia. In addition, we traced the fate of genetically labeled adult kidney collecting duct principal cells after Hes1 inactivation or lithium treatment.ResultsNotch signaling was required for maintenance of Aqp2-expressing cells in distal nephron and collecting duct segments in adult kidneys. Fate tracing revealed mature principal cells in the inner stripe of the outer medulla converted to intercalated cells after genetic inactivation of Hes1 and, to a lesser extent, lithium treatment. Hes1 ensured repression of Foxi1 to prevent the intercalated cell program from turning on in mature Aqp2+ cell types.ConclusionsNotch signaling viaHes1 regulates maintenance of mature renal epithelial cell states. Loss of Notch signaling or use of lithium can trigger transdifferentiation of mature principal cells to intercalated cells in adult kidneys.

scholarly journals Spatial Transcriptional Mapping of the Human Nephrogenic Program

2020 ◽  
Author(s):  
Nils O. Lindström ◽  
Rachel Sealfon ◽  
Xi Chen ◽  
Riana Parvez ◽  
Andrew Ransick ◽  
...  
Keyword(s):  
Gene Networks ◽  
Kidney Development ◽  
Three Dimensional ◽  
Human Kidney ◽  
Cell Types ◽  
Disease Genes ◽  
Network Mining ◽  
Spatially Resolved ◽  
Nephron Progenitors ◽  
Nephron Progenitor

SummaryCongenital abnormalities of the kidney and urinary tract are amongst the most common birth defects affecting 3% of newborns. The human kidney develops over a 30-week period in which a nephron progenitor pool gives rise to around a million nephrons. To establish a framework for human nephrogenesis, we spatially resolved a stereotypical process by which equipotent nephron progenitors generate a nephron anlagen, then applied data-driven approaches to construct three-dimensional protein maps on anatomical models of the nephrogenic program. Single cell RNA sequencing identified novel progenitor states which were spatially mapped to the nephron anatomy enabling the generation of functional gene-networks predicting interactions within and between nephron cell-types. Network mining identified known developmental disease genes and predicts new targets of interest. The spatially resolved nephrogenic program made available through the Human Nephrogenesis Atlas (https://sckidney.flatironinstitute.org/) will facilitate an understanding of kidney development and disease, and enhance efforts to generate new kidney structures.

scholarly journals Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Max Werth ◽  
Kai M Schmidt-Ott ◽  
Thomas Leete ◽  
Andong Qiu ◽  
Christian Hinze ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Notch Signaling ◽  
Salt Water ◽  
Collecting Duct ◽  
Cell Types ◽  
Nephron Segments ◽  
Collecting Ducts ◽  
Atpase Subunits ◽  
Central Characteristic ◽  
Salt And Pepper

Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments.

scholarly journals Foxi1 inactivation rescues loss of principal cell fate selection in Hes1-deficient kidneys but does not ensure maintenance of principal cell gene expression

2019 ◽  
Author(s):  
Malini Mukherjee ◽  
Jennifer DeRiso ◽  
Madhusudhana Janga ◽  
Eric Fogarty ◽  
Kameswaran Surendran
Keyword(s):  
Gene Expression ◽  
Notch Signaling ◽  
Cell Fate ◽  
Collecting Duct ◽  
Cell Types ◽  
Principal Cell ◽  
Intercalated Cell ◽  
Collecting Ducts ◽  
Cell Gene Expression ◽  
Cell Gene

AbstractThe distal nephron and collecting duct segments of the mammalian kidney consist of intercalated cell types intermingled among principal cell types. Notch signaling ensures that a sufficient number of cells select a principal instead of an intercalated cell fate. However, the precise mechanisms by which Notch signaling patterns the distal nephron and collecting duct cell fates is unknown. Here we observed that Hes1, a direct target of Notch signaling pathway, is required within the mouse developing collecting ducts for repression of Foxi1 expression, an essential intercalated cell specific transcription factor. Interestingly, inactivation of Foxi1 in Hes1-deficient collecting ducts rescues the deficiency in principal cell fate selection, overall urine concentrating deficiency, and reduces the occurrence of hydronephrosis. However, Foxi1 inactivation does not rescue the reduction in expression of all principal cell genes in the Hes1-deficient kidney collecting duct cells that select the principal cell fate. Additionally, suppression of Notch/Hes1 signaling in mature principal cells reduces principal cell gene expression without activating Foxi1. We conclude that Hes1 is a Notch signaling target that is essential for normal patterning of the collecting ducts with intermingled cell types by repressing Foxi1, and for maintenance of principal cell gene expression independent of repressing Foxi1.

Flexible-substratum technique for viewing cells from the side: some in vivo properties of primary (9+0) cilia in cultured kidney epithelia

1988 ◽  
Vol 89 (4) ◽  
pp. 457-466 ◽  
Author(s):  
K.E. Roth ◽  
C.L. Rieder ◽  
S.S. Bowser
Keyword(s):  
Epithelial Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Kidney Cell ◽  
Primary Cilia ◽  
Length Distribution ◽  
Cell Types ◽  
Phenotypic Marker ◽  
Kidney Epithelial Cell

Cells cultured on thin plastic (e.g. Formvar, Teflon, polycarbonate) membranes can be clearly imaged from the side in vivo by video microscopy. We have used this flexible-substratum technique to examine the behaviour and properties of primary cilia in confluent cultures of the kidney epithelial cell lines PtK1, PtK2, LLC-PK1, MDCK and BSC-40. In these cells primary cilia appear as rigid rods, up to 55 micron long, which project at various angles from the dorsal cell surface. The length distribution of primary cilia in confluent cultures is a distinct characteristic of each established kidney cell line examined, with LLC-PK1 exhibiting three distinct length populations. Primary cilia of kidney cell lines bend passively in response to flow but do not display propagated bending or vortical motions. Up to 26% of the cilia in the cell types examined possess one or more conspicuous swellings along the ciliary shaft. Treatment with 0.05% trypsin, which is sufficient to cause cell rounding, does not induce the resorption or shedding of the cilium. These direct observations demonstrate that kidney epithelial-cell primary cilia are non-motile and longer than previously thought, and suggest that their length represents a phenotypic marker for each cell line.

scholarly journals Branching morphogenesis in the developing kidney is not impacted by nephron formation or integration

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Kieran M Short ◽  
Alexander N Combes ◽  
Valerie Lisnyak ◽  
James G Lefevre ◽  
Lynelle K Jones ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Kidney Development ◽  
Developmental Process ◽  
Branching Morphogenesis ◽  
Ureteric Bud ◽  
Collecting Ducts ◽  
Developing Kidney ◽  
Developmental Feature ◽  
Nephron Progenitor ◽  
The Impact

Branching morphogenesis of the ureteric bud is integral to kidney development; establishing the collecting ducts of the adult organ and driving organ expansion via peripheral interactions with nephron progenitor cells. A recent study suggested that termination of tip branching within the developing kidney involved stochastic exhaustion in response to nephron formation, with such a termination event representing a unifying developmental process evident in many organs. To examine this possibility, we have profiled the impact of nephron formation and maturation on elaboration of the ureteric bud during mouse kidney development. We find a distinct absence of random branch termination events within the kidney or evidence that nephrogenesis impacts the branching program or cell proliferation in either tip or progenitor cell niches. Instead, organogenesis proceeds in a manner indifferent to the development of these structures. Hence, stochastic cessation of branching is not a unifying developmental feature in all branching organs.

scholarly journals The roles of histone deacetylases in kidney development and disease

2021 ◽  
Author(s):  
Hongbing Liu
Keyword(s):  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Kidney Diseases ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Developing Kidney ◽  
Nephron Progenitor ◽  
Class I Hdacs ◽  
Progression Of Renal Disease

AbstractHistone deacetylases (HDACs) are important epigenetic regulators that mediate deacetylation of both histone and non-histone proteins. HDACs, especially class I HDACs, are highly expressed in developing kidney and subject to developmental control. HDACs play an important role in kidney formation, especial nephron progenitor maintenance and differentiation. Several lines of evidence support the critical role of HDACs in the development and progression of various kidney diseases. HDAC inhibitors (HDACis) are very effective in the prevention and treatment of kidney diseases (including kidney cancer). A better understanting of the molecular mechanisms underlying the role(s) of HDACs in the pathogenesis and progression of renal disease are likely to be of great help in developing more effective and less toxic selective HDAC inhibitors and combinatorial therapeutics.

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