scholarly journals Centrosome amplification disrupts renal development and causes cystogenesis

2018 ◽  
Vol 217 (7) ◽  
pp. 2485-2501 ◽  
Author(s):  
Lai Kuan Dionne ◽  
Kyuhwan Shim ◽  
Masato Hoshi ◽  
Tao Cheng ◽  
Jinzhi Wang ◽  
...  
Keyword(s):  
Mitotic Spindle ◽  
Kidney Development ◽  
Branching Morphogenesis ◽  
Centrosome Amplification ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Renal Hypoplasia ◽  
Developmental Defects ◽  
Renal Progenitors

Centrosome number is tightly controlled to ensure proper ciliogenesis, mitotic spindle assembly, and cellular homeostasis. Centrosome amplification (the formation of excess centrosomes) has been noted in renal cells of patients and animal models of various types of cystic kidney disease. Whether this defect plays a causal role in cystogenesis remains unknown. Here, we investigate the consequences of centrosome amplification during kidney development, homeostasis, and after injury. Increasing centrosome number in vivo perturbed proliferation and differentiation of renal progenitors, resulting in defective branching morphogenesis and renal hypoplasia. Centrosome amplification disrupted mitotic spindle morphology, ciliary assembly, and signaling pathways essential for the function of renal progenitors, highlighting the mechanisms underlying the developmental defects. Importantly, centrosome amplification was sufficient to induce rapid cystogenesis shortly after birth. Finally, we discovered that centrosome amplification sensitized kidneys in adult mice, causing cystogenesis after ischemic renal injury. Our study defines a new mechanism underlying the pathogenesis of renal cystogenesis, and identifies a potentially new cellular target for therapy.

scholarly journals Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model

2018 ◽  
Vol 115 (49) ◽  
pp. 12489-12494 ◽  
Author(s):  
Simon A. Ramsbottom ◽  
Elisa Molinari ◽  
Shalabh Srivastava ◽  
Flora Silberman ◽  
Charline Henry ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Exon Skipping ◽  
Joubert Syndrome ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Kidney Cells ◽  
Promising Therapeutic Approach

Genetic treatments of renal ciliopathies leading to cystic kidney disease would provide a real advance in current therapies. Mutations in CEP290 underlie a ciliopathy called Joubert syndrome (JBTS). Human disease phenotypes include cerebral, retinal, and renal disease, which typically progresses to end stage renal failure (ESRF) within the first two decades of life. While currently incurable, there is often a period of years between diagnosis and ESRF that provides a potential window for therapeutic intervention. By studying patient biopsies, patient-derived kidney cells, and a mouse model, we identify abnormal elongation of primary cilia as a key pathophysiological feature of CEP290-associated JBTS and show that antisense oligonucleotide (ASO)-induced splicing of the mutated exon (41, G1890*) restores protein expression in patient cells. We demonstrate that ASO-induced splicing leading to exon skipping is tolerated, resulting in correct localization of CEP290 protein to the ciliary transition zone, and restoration of normal cilia length in patient kidney cells. Using a gene trap Cep290 mouse model of JBTS, we show that systemic ASO treatment can reduce the cystic burden of diseased kidneys in vivo. These findings indicate that ASO treatment may represent a promising therapeutic approach for kidney disease in CEP290-associated ciliopathy syndromes.

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 Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development

2018 ◽  
Vol 151 ◽  
pp. 10-17 ◽  
Author(s):  
Paurav B. Desai ◽  
Jovenal T. San Agustin ◽  
Michael W. Stuck ◽  
Julie A. Jonassen ◽  
Carlton M. Bates ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Development ◽  
Disease Gene ◽  
Cystic Kidney Disease ◽  
Cystic Kidney

scholarly journals A Tissue-Bioengineering Strategy for Modeling Rare Human Kidney Diseases In Vivo

2021 ◽  
Author(s):  
Joel Hernandez ◽  
Xichi Wang ◽  
Miriam Vazquez-Segoviano ◽  
Maria Fernanda Sobral-Reyes ◽  
Alejandro Moran-Horowich ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Kidney Diseases ◽  
Human Kidney ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Cell Phenotype ◽  
Mtor Inhibition ◽  
Transcriptional Signature ◽  
Kidney Organoids

The lack of animal models for certain human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here we generated kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs to recapitulate a rare kidney tumor called angiomylipoma (AML). Organoids derived from TSC2-/- hiPSCs but not from isogenic TSC2+/- or TSC2+/+ hiPSCs shared a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and developed epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be robustly and consistently recapitulated with transgenic mice. Transplantation of multiple TSC2-/- kidney organoids into the kidneys of immunodeficient rats allowed us to recapitulate AML and cystic kidney disease in vivo, in a scalable fashion and with fidelity, and to test the efficiency of rapamycin-loaded nanoparticles as a novel approach to ablate AMLs by inducing apoptosis triggered by mTOR-inhibition. Collectively, these methods represent a novel tissue-bioengineering strategy for rare disease modeling in vivo.

scholarly journals Midkine Is Involved in Kidney Development and in Its Regulation by Retinoids

2002 ◽  
Vol 13 (3) ◽  
pp. 668-676
Author(s):  
José Vilar ◽  
Claude Lalou ◽  
Jean-Paul Duong Van Huyen ◽  
Stéphanie Charrin ◽  
Sylvie Hardouin ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Neutralizing Antibodies ◽  
Kidney Development ◽  
Vitamin A Deficiency ◽  
Branching Morphogenesis ◽  
Defined Medium ◽  
Dependent Manner ◽  
Heparin Binding

ABSTRACT. In the kidney, in which development depends on epithelial-mesenchymal interactions, it has been shown that retinoids modulate nephrogenesis in a dose-dependent manner in vivo and in vitro. Midkine (MK) is a retinoic acid responsive gene for a heparin-binding growth factor. The aim of the present study was therefore to quantify the expression of MK mRNA during renal development in the rat, to analyze the regulation of MK expression by retinoids in vivo and in vitro, and, finally, to study the role of MK in rat metanephric organ cultures. The spatiotemporal expression of MK in fetal kidney was studied. In control rats, MK expression is ubiquitous at gestational day 14, i.e., at the onset of nephrogenesis. On day 16, MK is expressed in the condensed mesenchyme and in early epithelialized mesenchymal derivatives. On gestational day 21, MK is rather localized in the nonmature glomeruli of the renal cortex. In utero exposure to vitamin A deficiency did not modify the specific spatial and temporal expression pattern of MK gene in the metanephros, although a decrease in mRNA expression occurred. In metanephroi explanted from 14-d-old fetuses and cultured in a defined medium, expression of MK mRNA was found to be stimulated when retinoic acid (100 nM) was added in the culture medium. Finally, in vitro nephrogenesis was strongly inhibited in the presence of neutralizing antibodies for MK: the number of nephrons formed in vitro was reduced by ∼50% without changes in ureteric bud branching morphogenesis. These results indicated that MK is implicated in the regulation of kidney development by retinoids. These results also suggested that MK plays an important role in the molecular cascade of the epithelial conversion of the metanephric blastema.

scholarly journals Temporally and Spatially Regulated Collagen XVIII Isoforms Impact Ureteric Patterning Through Their TSP1-like Domain

2021 ◽  
Author(s):  
Mia M. Rinta-Jaskari ◽  
Florence Naillat ◽  
Heli J. Ruotsalainen ◽  
Saad U. Akram ◽  
Jarkko T. Koivunen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Kidney Development ◽  
Ex Vivo ◽  
Branching Morphogenesis ◽  
Tight Control ◽  
Collagen Xviii ◽  
Signalling Network ◽  
Renal Progenitors ◽  
Nephron Progenitor ◽  
And Control

ABSTRACTCollagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of homeostasis. We provide evidence that ColXVIII has a specific role in kidney ontogenesis by regulating the interaction between mesenchymal and epithelial tissues as observed in analyses of total and isoform-specific knockout embryos, mice, andex vivoorgan primordia. ColXVIII deficiency, both temporally and spatially, impacts the 3D pattern of ureteric tree branching morphogenesisviaits specific isoforms. Proper development of ureteric tree depends on a tight control of the nephron progenitor cells (NPCs). ColXVIII-deficient NPCs are leaving the NPC pool faster than in controls. Moreover, the data suggests that ColXVIII mediates the kidney epithelial tree patterningviaits N-terminal domains, and especially the Thrombospondin-1-like domain, and that this morphogenetic effect involves ureteric epithelial integrins. Altogether, the results propose a significant role for ColXVIII in a complex signalling network regulating renal progenitors and kidney development.

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.

Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies

2007 ◽  
Vol 293 (2) ◽  
pp. F548-F554 ◽  
Author(s):  
Reetu R. Singh ◽  
Karen M. Moritz ◽  
John F. Bertram ◽  
Luise A. Cullen-McEwen
Keyword(s):  
Gene Expression ◽  
Kidney Development ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Branching Morphogenesis ◽  
In Vivo Studies ◽  
Nephron Endowment ◽  
Tgf Β1

Maternal administration of dexamethasone (DEX) for 48 h early in rat kidney development results in offspring with a reduced nephron endowment. However, the mechanism through which DEX inhibits nephrogenesis is unknown. In this study, we hypothesized that DEX may indirectly inhibit nephrogenesis by inhibiting ureteric branching morphogenesis. Whole metanephroi from embryonic day 14.5 ( E14.5) rat embryos were cultured in the presence of DEX. DEX (10−5 M) exposure for 2 days significantly inhibited ureteric branching compared with metanephroi grown in control media or DEX (10−7 M). Culturing metanephroi for a further 3 days (in control media only) reduced total glomerular number in metanephroi previously exposed to DEX (10−5 M) or (10−7 M) compared with control cultures. Expression of genes known to regulate ureteric branching morphogenesis was determined by real-time PCR in metanephroi after 2 days in culture. DEX exposure in vitro decreased expression of glial cell line-derived neurotrophic factor (GDNF) and increased expression of bone morphogenetic protein-4 (BMP-4) and transforming growth factor-β1 (TGF-β1). Similar gene expression changes were found in E16.5 metanephroi in which the dam had been exposed to 2 days of DEX (0.2 mg·kg−1·day−1) at E14.5/15.5 in vivo. However, in kidneys collected at E20.5 after in vivo exposure for 2 days, GDNF expression was increased and BMP-4 and TGF-β1 expression decreased suggesting a biphasic response in gene expression to DEX exposure. These results show for the first time that inhibition of ureteric branching morphogenesis may be a key mechanism through which DEX exposure results in a reduced nephron endowment.

scholarly journals Renal oligohydramnios and Potter sequence with cystic kidney disease

2021 ◽  
Vol 66 (1) ◽  
pp. 47-51
Author(s):  
E. F. Andreeva ◽  
N. D. Savenkova
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Renal Dysplasia ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Renal Hypoplasia ◽  
Characteristic Appearance ◽  
Potter Sequence ◽  
Renal Oligohydramnios

For the first time in 1946 E.L. Potter (1901–1993) described the characteristic appearance of stillborns and deceased newborns with bilateral renal agenesis. Due to the further observations Potter distinguished the syndrome (Q60.6) – a set of characteristic external signs that are formed due to the extreme degree of oligohydramnios and intrauterine compression of the fetus. Classical Potter syndrome is diagnosed by the disfunction of both kidneys in the fetus (for example, bilateral agenesis), which leads to death. The term «Potter sequence» or oligohydramnios sequence with diverse causes has received the wide clinical use. The term «renal oligohydramnios» (ROH) is used to describe oligohydramnios resulting from a decrease or absence of fetal kidney function. The authors state that renal oligohydramnios and Potter sequence often develop in the fetus with cystic kidney disease with the formation of cysts in the parenchyma of both kidneys (autosomal recessive polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulocystic kidney disease associated with HNF1ß/TCF2 gene mutations, renal-coloboma syndrome, cystic renal hypoplasia, cystic renal dysplasia with mutations of the CEP55 gene).

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