Identification and characterization of retinoic acid‐responsive genes in mouse kidney development

Takayama, Mami; Miyatake, Koichi; Nishida, Eisuke

doi:10.1111/gtc.12163

Cited by 17 publications

(24 citation statements)

References 46 publications

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“…S2 ). Notably, similar or identical concentrations of these compounds were previously successfully used in kidney explants and other organ contexts to manipulate RA signaling 13 , 16 – 18 .…”

Section: Resultsmentioning

confidence: 99%

“…RA from the pericloacal mesenchyme regulates ureter-bladder connectivity by inducing apoptosis of the most distal aspect of the nephric duct 11 . RA signaling is active in the renal stroma to regulate branching morphogenesis 12 , 13 . Studies in the bladder have recently uncovered a role for the signal in urothelial specification 14 .…”

Section: Introductionmentioning

confidence: 99%

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Retinoic acid signaling maintains epithelial and mesenchymal progenitors in the developing mouse ureter

Bohnenpoll

Weiss

Labuhn

et al. 2017

Sci Rep

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The differentiated cell types of the mature ureter arise from the distal ureteric bud epithelium and its surrounding mesenchyme. Uncommitted epithelial cells first become intermediate cells from which both basal and superficial cells develop. Mesenchymal progenitors give rise to separated layers of adventitial fibrocytes, smooth muscle cells and lamina propria fibrocytes. How progenitor expansion and differentiation are balanced is poorly understood. Here, we addressed the role of retinoic acid (RA) signaling in these programs. Using expression analysis of components and target genes, we show that pathway activity is restricted to the mesenchymal and epithelial progenitor pools. Inhibition of RA signaling in ureter explant cultures resulted in tissue hypoplasia with a relative expansion of smooth muscle cells at the expense of lamina propria fibroblasts in the mesenchyme, and of superficial cells at the expense of intermediate cells in the ureteric epithelium. Administration of RA led to a slight reduction of smooth muscle cells, and almost completely prevented differentiation of intermediate cells into basal and superficial cells. We identified cellular programs and transcriptional targets of RA signaling that may account for this activity. We conclude that RA signaling is required and sufficient to maintain mesenchymal and epithelial progenitors in early ureter development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retinoic acid signaling maintains epithelial and mesenchymal progenitors in the developing mouse ureter

Bohnenpoll

Weiss

Labuhn

et al. 2017

Sci Rep

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“…Expression of p65 was high in both Lewis and LPK kidneys in early life, suggesting that a basal level of NF-κB activation may be required for development in the normal kidney. Indeed, NF-κB inhibition in ex vivo embryonic kidneys has been shown to impair ureteric bud branching, which is critical for collecting duct development [38,39] . Whereas in Lewis rats p65 expression was low from week 10 onwards, in LPK rats the high expression of p65 was sustained throughout life.…”

Section: Discussionmentioning

confidence: 99%

Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

Schwensen

Liuwantara

et al. 2016

WJN

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Author contributions: Schwensen KG conducted the animal study, performed sample collection and histological staining; Ta MHT performed the immunofluorescence, Western blotting, and qPCR experiments, analyzed data and drafted the manuscript; Huso DL and Watnick T developed the Pkd2 knockout mouse model and provided paraffin embedded sections that were utilized for staining; Liuwantara D assisted with data interpretation and provided technical guidance with experimental methods; Rangan GK conceived of the study, conducted the animal study, performed sample collection and histological staining and reviewed and edited the manuscript; all authors read and approved of the final manuscript. Supported by Basic Study(LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mRNA expression of NF-κB-dependent genes (TNFa and CCL2) were determined. NF-κB was also histologically assessed in human PKD tissue. RESULTS:Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation (peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis (with a smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-κB proteins (phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells (CECs) of LPK kidneys as early as postnatal week 3 and sustained until latestage disease at week 20. From weeks 10 to 20, nuclear p65, p50, RelB and cytoplasmic IκBa protein levels, and TNFa and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-κB proteins were consistently expressed in CECs of human PKD. The DNA damage marker γ-H2AX was also identified in the CECs of LPK and human polycystic kidneys. CONCLUSION:Several NF-κB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF-κB signaling may be a constitutive and early pathological feature of cystic renal diseases. Core tip: Until now, there has been limited information regarding the specific nuclear factor (NF)-κB proteins involved in polycystic kidney disease (PKD) and their expression throughout disease progression. Our study demonstrated that a diverse array of NF-κB proteins is expressed in the renal cyst-lining cells of a chronic rodent model of PKD, and that NF-κB expression is constitutive over time. NF-κB was also identified in human PKD, suggesting that NF-κB upregulation is common to renal cystic disease models. Our data suggest that components of both the canonical and non-canonical NF-κB pathway are upregulated in PKD. Future studies should be directed at verifying whether specific NF-κB inhibition can attenuate interstitial inflammation and cyst growth, and slow the decline in renal function in in vivo models of PKD.Ta MHT, Schwensen KG, Liuwantara D, Huso DL, Watnick T, Rangan GK. Con...

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“…The role of retinoic acid signaling in ureteric bud branching morphogenesis has been further established in the in vitro organ-culture model, where embryonic kidneys cultured in the absence of retinoic acid showed significantly reduced ureteric bud branching and decreased Ret expression compared to its counterparts cultured in the presence of retinoic acid (Moreau et al, 1998;Vilar et al, 1996;Takayama et al, 2014). Retinoic acid signaling regulates Ret expression in a cell-autonomous manner in the ureteric tip cells, likely by directly activating its transcription Molecular Reproduction & Development (Moreau et al, 1998;Rosselot et al, 2010;Stine et al, 2011;Takayama et al, 2014).…”

Section: Roles Of Renal Interstitial Cells In Ureteric Bud Branchingmentioning

confidence: 99%

The ureteric bud epithelium: Morphogenesis and roles in metanephric kidney patterning

Nagalakshmi

2015

Molecular Reproduction Devel

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The mammalian metanephric kidney is composed of two epithelial components –the collecting duct system and the nephron epithelium– that differentiate from two different tissues –the ureteric bud epithelium and the nephron progenitors, respectively– of intermediate mesoderm origin. The collecting duct system is generated through reiterative ureteric bud branching morphogenesis whereas the nephron epithelium is formed in a process termed nephrogenesis, which is initiated with the mesenchymal-epithelial transition of the nephron progenitors. Ureteric bud branching morphogenesis is regulated by nephron progenitors, and in return the ureteric bud epithelium regulates nephrogenesis. The metanephric kidney is also physiologically divided along the cortico-medullary axis into subcompartments that are enriched with specific segments of these two epithelial structures. Here we provide an overview of the major molecular and cellular processes underlying the morphogenesis and patterning of the ureteric bud epithelium and its roles in the cortical-medullary patterning of the metanephric kidney.

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Identification and characterization of retinoic acid‐responsive genes in mouse kidney development

Cited by 17 publications

References 46 publications

Retinoic acid signaling maintains epithelial and mesenchymal progenitors in the developing mouse ureter

Retinoic acid signaling maintains epithelial and mesenchymal progenitors in the developing mouse ureter

Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

The ureteric bud epithelium: Morphogenesis and roles in metanephric kidney patterning

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