Glycogen Synthase Kinase-3 Inactivation and Stabilization of β-Catenin Induce Nephron Differentiation in Isolated Mouse and Rat Kidney Mesenchymes

Kuure, Satu; Popsueva, Anna; Jakobson, Madis; Sainio, Kirsi; Sariola, Hannu

doi:10.1681/asn.2006111206

Cited by 126 publications

(127 citation statements)

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“…The ex vivo and in vivo evidence indicates that in the embryonic kidney, the induction process involves Wnts, and they are sufficient to trigger the nephrogenesis developmental programme [12]. Indeed, the nephrogenesis process can also be induced with a small-molecule lithium chloride or BIO that serves downstream activators of the Wnt signalling pathway [15,52,53]. Based on our data, exosomes purified from the inductive UB failed to induce nephrogenesis.…”

Section: Discussionmentioning

confidence: 83%

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Exosomes as secondary inductive signals involved in kidney organogenesis

Krause

Rak-Raszewska

Naillat

et al. 2018

J of Extracellular Vesicle

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The subfraction of extracellular vesicles, called exosomes, transfers biological molecular information not only between cells but also between tissues and organs as nanolevel signals. Owing to their unique properties such that they contain several RNA species and proteins implicated in kidney development, exosomes are putative candidates to serve as developmental programming units in embryonic induction and tissue interactions. We used the mammalian metanephric kidney and its nephron-forming mesenchyme containing the nephron progenitor/stem cells as a model to investigate if secreted exosomes could serve as a novel type of inductive signal in a process defined as embryonic induction that controls organogenesis. As judged by several characteristic criteria, exosomes were enriched and purified from a cell line derived from embryonic kidney ureteric bud (UB) and from primary embryonic kidney UB cells, respectively. The cargo of the UB-derived exosomes was analysed by qPCR and proteomics. Several miRNA species that play a role in Wnt pathways and enrichment of proteins involved in pathways regulating the organization of the extracellular matrix as well as tissue homeostasis were identified. When labelled with fluorescent dyes, the uptake of the exosomes by metanephric mesenchyme (MM) cells and the transfer of their cargo to the cells can be observed. Closer inspection revealed that besides entering the cytoplasm, the exosomes were competent to also reach the nucleus. Furthermore, fluorescently labelled exosomal RNA enters into the cytoplasm of the MM cells. Exposure of the embryonic kidney-derived exosomes to the whole MM in an ex vivo organ culture setting did not lead to an induction of nephrogenesis but had an impact on the overall organization of the tissue. We conclude that the exosomes provide a novel signalling system with an apparent role in secondary embryonic induction regulating organogenesis.

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Section: Discussionmentioning

confidence: 83%

“…While the UB is a natural MM nephrogenesis inducer, it can be removed and replaced by chemical activation of the Wnt pathway via the GSK-3 inhibitor (BIO) [15] in the process of renal organoid formation [16]. …”

Section: Introductionmentioning

confidence: 99%

Exosomes as secondary inductive signals involved in kidney organogenesis

Krause

Rak-Raszewska

Naillat

et al. 2018

J of Extracellular Vesicle

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“…The fact that Wnt4 expression in the rat kidney appears to be independent of the ureteric bud may partially explain why Lif is sufficient to induce tubulogenesis in the rat but not in the mouse, where Wnt4 appears to be dependent on a signal from the bud. It is interesting to note that canonical Wnt signaling appears to be sufficient to induce tubulogenesis in mesenchyme isolated from mouse mutants that do not form a caudal Wolffian duct or ureteric bud (Gata3 and Gdnf mutants, respectively) and, therefore, have never been exposed to any other duct/bud derived signals [51]. These data are suggestive that canonical Wnt signaling acts alone in tubule formation and that other sufficient factors are either acting through the Wnt pathway or through some other mechanism.…”

Section: Wnts In Renal Vesicle Formationmentioning

confidence: 99%

Molecular regulation of kidney development: is the answer blowing in the Wnt?

2007

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Development of the metanephric kidney is a complicated process regulated by reciprocal signals from the ureteric bud and the metanephric mesenchyme that regulate tubule formation and epithelial branching morphogenesis. Over the past several years, several studies have suggested that Wnt signaling is involved in multiple aspects of normal kidney development as well as injury response and cancer progression. We will review these data here.

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“…Recent evidence suggests a role of PI3K for the maintenance of progenitor cells as well (14). The multifunctional protein β-catenin mediates canonical Wnt signaling, and is necessary for both nephrogenesis and ureteric branching (15,16).In the present study, we investigated whether inhibited ureteric bud branching and or early cessation of nephrogenesis is a mechanism for the reduced nephron number by maternal nutrient restriction. We also studied whether signaling pathways important in kidney development are altered.…”

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confidence: 94%

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confidence: 99%

Maternal nutrient restriction inhibits ureteric bud branching but does not affect the duration of nephrogenesis in rats

Awazu

Hida

2015

Pediatr Res

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Background: Maternal nutrient restriction produces offspring with fewer nephrons. We studied whether the reduced nephron number is due to the inhibition of ureteric branching or early cessation of nephrogenesis in rats. Signaling pathways involved in kidney development were also examined. Methods: The offspring of dams given food ad libitum (control (CON)) and those subjected to 50% food restriction (nutrient restriceted (NR)) were examined. results: At embryonic day 13 (E13), there was no difference between NR and CON in body weight or kidney size. Ureteric buds branched once in both NR and CON. At E14 and E15, body and kidney size were significantly reduced in NR. Ureteric bud tip numbers were also reduced to 50% of CON. On the other hand, the disappearance of nephrogenic zone and a nephron progenitor marker Cited1 was not different between CON and NR. The final glomerular number of NR was 80% of CON. Activated extracellular signal-regulated kinase (ERK), p38, PI3K, Akt, and mammallian target of rapamycin (mTOR), and protein expression of β-catenin were downregulated at E15. conclusion: Ureteric branching is inhibited and developmentally regulated signaling pathways are downregulated at an early stage by maternal nutrient restriction. These changes, not early cessation of nephrogenesis, may be a mechanism for the inhibited kidney growth and nephrogenesis. t he concept that disturbed intrauterine organogenesis affects the health and disease in the adulthood, termed developmental origins of health and disease, has been increasingly recognized. With respect to the kidney, low birth weight is associated with a risk for hypertension and renal disease, and reduced nephron number is considered to be the cause. In animals, maternal protein or global nutrient restriction, uterine artery ligation, hyperglycemia, and exposure to various agents such as glucocorticoids or alcohol produce offspring with fewer nephrons (1-6). Depletion of stem cells by increased apoptosis has been suggested to be responsible for the decreased nephron formation (1,3). On the other hand, ureteric bud branching is a fundamental step in determining nephron number. The mechanism of reduced nephron endowment in dexamethasone or ethanol exposure has been suggested to be inhibited branching morphogenesis in an organ culture study (5,7). Reduced ureteric branching has recently been reported in a model of maternal hyperglycemia in vivo (8).Another possible mechanism of reduced nephron number is early cessation of nephrogenesis. In human premature infants, nephrogenesis is reported to continue only up to 40 d after birth (9). These infants are under various stresses including hypoxia, infection, and medications adversely affecting nephrogenesis. It has been postulated that adverse conditions during development promote differentiation aiming at early maturation and survival at the expense of reduced organ growth. Newborn rats resemble human premature neonates in that nephrogenesis continues after birth. Early cessation of nephrogenesis, therefore, may b...

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Glycogen Synthase Kinase-3 Inactivation and Stabilization of β-Catenin Induce Nephron Differentiation in Isolated Mouse and Rat Kidney Mesenchymes

Cited by 126 publications

References 59 publications

Exosomes as secondary inductive signals involved in kidney organogenesis

Exosomes as secondary inductive signals involved in kidney organogenesis

Molecular regulation of kidney development: is the answer blowing in the Wnt?

Maternal nutrient restriction inhibits ureteric bud branching but does not affect the duration of nephrogenesis in rats

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