Retinoids and Renal Development

Burrow, Christopher R.

doi:10.1159/000020672

Cited by 40 publications

(20 citation statements)

References 47 publications

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“…Besides RAR/RXR heterodimerization, RXR also heterodimerizes with thyroid receptors, vitamin D receptors, peroxisome proliferatoractivator receptors and other ligand-activated nuclear receptors. RXR and RAR are recognized to play important roles in renal development especially in structures derived from the ureteric bud (25). RXR-binding motifs were substantially and significantly more common in 5Ј-flanking regions of IMCD-specific genes than in other genes expressed in PT, MTAL or IMCD (Table S5) consistent with a role as a determinant of cell-specific gene expression in the collecting duct.…”

Section: Discussionmentioning

confidence: 77%

Systems-level analysis of cell-specific AQP2 gene expression in renal collecting duct

Miller

Uawithya

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

139

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We used a systems biology-based approach to investigate the basis of cell-specific expression of the water channel aquaporin-2 (AQP2) in the renal collecting duct. Computational analysis of the 5-flanking region of the AQP2 gene (Genomatix) revealed 2 conserved clusters of putative transcriptional regulator (TR) binding elements (BEs) centered at ؊513 bp (corresponding to the SF1, NFAT, and FKHD TR families) and ؊224 bp (corresponding to the AP2, SRF, CREB, GATA, and HOX TR families). Three other conserved motifs corresponded to the ETS, EBOX, and RXR TR families. To identify TRs that potentially bind to these BEs, we carried out mRNA profiling (Affymetrix) in mouse mpkCCDc14 collecting duct cells, revealing expression of 25 TRs that are also expressed in native inner medullary collecting duct. One showed a significant positive correlation with AQP2 mRNA abundance among mpkCCD subclones (Ets1), and 2 showed a significant negative correlation (Elf1 and an orphan nuclear receptor Nr1h2). Transcriptomic profiling in native proximal tubules (PT), medullary thick ascending limbs (MTAL), and IMCDs from kidney identified 14 TRs (including Ets1 and HoxD3) expressed in the IMCD but not PT or MTAL (candidate AQP2 enhancer roles), and 5 TRs (including HoxA5, HoxA9 and HoxA10) expressed in PT and MTAL but not in IMCD (candidate AQP2 repressor roles). In luciferase reporter assays, overexpression of 3 ETS family TRs transactivated the mouse proximal AQP2 promoter. The results implicate ETS family TRs in cell-specific expression of AQP2 and point to HOX, RXR, CREB and GATA family TRs as playing likely additional roles.aquaporin 2 ͉ kidney ͉ microarrays ͉ transcription ͉ vasopressin R enal water excretion is tightly regulated chiefly through effects of vasopressin on the molecular water channel, aquaporin-2 (AQP2) (1). AQP2 gene expression in the kidney is restricted to collecting duct principal cells and connecting tubule cells (2, 3). Aside from control of trafficking of AQP2-containing vesicles (1), AQP2 is regulated through changes in the total abundance of the AQP2 protein in collecting duct cells. Vasopressin increases the renal abundance of the AQP2 protein (4) via changes in AQP2 mRNA levels (5), in part by transcriptional regulation. Studies in transgenic mice in which 14-15 kb of the 5Ј-flanking region of the AQP2 gene was coupled to reporters established that cell-specific expression of the AQP2 gene in the collecting duct is dependent on cis-elements in this region (6, 7). Altered AQP2 protein abundance in the renal collecting duct is largely responsible for water balance abnormalities associated with diverse clinical states including lithium-induced diabetes insipidus, congestive heart failure, and the syndrome of inappropriate antidiuresis (1). Understanding the roles of AQP2 in these clinical states hinges largely on understanding the mechanism of cell-specific expression of the AQP2 gene.Sequencing of the 5Ј-flanking region of the AQP2 gene revealed several putative cis-binding element (BE) motifs including a c...

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Section: Discussionmentioning

confidence: 77%

Systems-level analysis of cell-specific AQP2 gene expression in renal collecting duct

Miller

Uawithya

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

139

View full text Add to dashboard Cite

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“…It has long been appreciated that retinoids play an essential role in kidney organogenesis (Burrow, 2000). The RARb2 and RARb4 isoforms are frequently methylated in lung, breast and prostate cancers (Virmani et al, 2000;Maruyama et al, 2002), but neither we nor Harada et al (2002a) detected de novo methylation of their promoter (P2) in Wilms' tumour.…”

Section: Discussionmentioning

confidence: 94%

Multigene methylation analysis of Wilms' tumour and adult renal cell carcinoma

et al. 2003

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To investigate the role of epigenetic gene silencing in the pathogenesis of Wilms' tumour and renal cell carcinoma (RCC), we determined their methylation profile using a candidate gene approach. Thus, 40 Wilms' tumours and up to 49 adult RCC were analysed by methylation-specific PCR for promoter methylation at CASP8, CDH1, CDH13, DAPK, MGMT, NORE1A, p14 ARF and RARB2 in primary Wilms' tumours and CASP8, CDH1, CDH13, CRBP1, DAPK, MGMT, MT1G, NORE1A, p16 INK4a , SDHB and RARB2 in primary RCC. Both tumour sample sets had previously been analysed for RASSF1A promoter methylation, and p16 INK4a methylation results were also available for the Wilms' tumour samples. Wilms' tumours demonstrated a high incidence of methylation at CASP8 (43%) and MGMT (30%), intermediate frequencies at NORE1A (15%), p14 ARF (15%), p16 INK4a (10%), DAPK (11%) and CRBP1 (9%), but promoter methylation was rare or absent at RARB2 (0%), CDH13 (0%) and CDH1 (3%). No association was detected between methylation of RASSF1A, CASP8 or MGMT in individual tumours. The frequency of MGMT methylation was higher in stage 1 and 2 tumours (50%) than in stage 3 and 4 tumours (17%) but this did not reach statistical significance (P ¼ 0.06). RCC were most frequently methylated at DAPK (24%), MT1G (20%), NORE1A (19%), CDH1 (16%) and MGMT (9%) and not or rarely at SDHB (4%), RARB2 (0%), p16 INK4a (0%) and CDH13 (3%). There were no associations between methylation of RASSF1A, DAPK and CDH1 in individual tumours. Papillary RCC demonstrated a higher frequency of DAPK methylation (43%) than clear cell tumours (19%) (P ¼ 0.14). We have demonstrated that de novo promoter methylation is frequent in Wilms' tumour and RCC, and these data enable methylation profiles to be constructed for each tumour type. Thus, combining our results with data published previously, it appears that promoter methylation occurs frequently (X20% of primary tumours) at CASP8, SLIT2 and RASSF1A in Wilms' tumour and at RASSF1A, TIMP3, DAPK, SLIT2, MT1G and GSTP1 in RCC.

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“…Therefore, it can be anticipated that investigation into the direct target genes affected by RA signalling will further advance our understanding of the role of retinoids in renal development. Midkine, sonic hedgehog, Hox d-11, matrix metalloproteinases, and tissue inhibitors of metalloproteinases have all been proposed as potential targets of interest [55], but their exact roles are still to be defined. For example, the midkine promoter contains a functional RARE [56], and midkine expression is reduced in vitamin A deficiency [57].…”

Section: Retinoids In Renal Development: Physiologic and Pharmacologimentioning

confidence: 99%