Pax-2, kidney development, and oncogenesis

Dressler, Gregory R.

doi:10.1002/(sici)1096-911x(199611)27:5<440::aid-mpo9>3.0.co;2-m

Cited by 42 publications

(21 citation statements)

References 27 publications

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“…Thus, the examination of the functional role of HHIP during the entire period of Alternatively, the heightened HHIP expression might alter the SHH-controlled expression of kidney formation genes, such as Pax2, Sall1, Mycn, Ccnd1, Gli1 and Gli2 [14], in the nephrogenic zone, subsequently resulting in the development of renal abnormalities. For instance, Pax2 as a 'kidney-specific' master gene is expressed in both UB and MM lineages, normally optimising UB branching and mesenchymal-toepithelial transition during kidney development [27][28][29]. Mutations or deficiency of Pax2 cause an increase in cellular apoptosis [30][31][32], associated with renal hypoplasia [30,33,34].…”

Section: Discussionmentioning

confidence: 99%

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

et al. 2014

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Aims/hypothesis We hypothesised that maternal diabetes impairs kidney formation in offspring via augmented expression of hedgehog interacting protein (HHIP). Our gene-array results were performed in neonatal kidneys from our murine model of maternal diabetes and indicated that Hhip expression was significantly modulated by maternal diabetes. Methods We systematically examined the functional role of HHIP in kidney formation in our murine maternal diabetes model and elucidated the potential mechanisms related to dysnephrogenesis in vitro. Results The kidneys of the offspring of diabetic dams, compared with those of the offspring of control non-diabetic dams, showed retardation of development-small kidneys and less ureteric bud (UB) branching morphogenesis. Augmented HHIP expression was observed in the offspring of diabetic dams, initially localised to differentiated metanephric mesenchyme and UB epithelium and subsequently in maturing glomerular endothelial and tubulointerstitial cells. The heightened HHIP targeting TGF-β1 signalling was associated with dysmorphogenesis. In vitro, HHIP overexpression decreased sonic hedgehog and paired box gene 2 proteins (SHH and PAX2, respectively) and increased transcriptional nuclear factor-kappa B (NFκB, p50/p65), phosphorylation of p53, and TGF-β1 expression. In contrast, overexpression of PAX2 inhibited HHIP and NFκB and activated SHH, N-myc and p27Kip1 expression. Moreover, high glucose stimulated HHIP expression, and then targeted TGF-β1 signalling. Thus, PAX2, via a negative autocrine feedback mechanism, attenuated the stimulatory effect of high glucose on HHIP expression. Conclusions/interpretation Maternal diabetes modulates kidney formation in young progeny mediated, at least in part, via augmented HHIP expression.

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Section: Discussionmentioning

confidence: 99%

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

et al. 2014

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“…The Pax-2 gene, a mammalian homeobox gene, encodes for a transcription factor that is essential for the conversion of cells of the metanephric mesenchyme to the renal vesicle. Gene knock-out experiments show that in the absence of this factor no formation of the vesicle occurs (98,376,465). The further differentiation of these early epithelial cells and their maturation to podocytes is then correlated with the decrease of PAX-2 and the rise of WT-1 expression, suggesting that WT-1 may negatively regulate PAX-2 expression (381).…”

Section: Developmental Aspectsmentioning

confidence: 99%

Cell Biology of the Glomerular Podocyte

Pavenstädt

Kriz

Kretzler

2003

Physiological Reviews

1,322

1,278

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Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.

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“…As a "kidney-specific" master gene, Pax-2 is expressed in both ureteric bud (UB) and metanephric mesenchyme (MM) lineages, normally optimizing UB branching and mesenchymal-to-epithelial transformation in kidney development. [12][13][14] Mutations in the Pax-2 gene cause increased apoptosis, [15][16][17] associated with renal hypoplasia. 15,18,19 We recently reported that high D(ϩ) glucose (25 mM), as compared with normal glucose (5 mM), specifically induced Pax-2 gene expression in both in vitro (mouse metanephric mesenchymal cells [MK4]) and ex vivo (kidney explant from Hoxb7-green fluorescence protein [Hox7-GFP] mice) models.…”

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confidence: 99%

Reactive Oxygen Species in the Presence of High Glucose Alter Ureteric Bud Morphogenesis

Zhang

Chen

Tran

et al. 2007

Journal of the American Society of Nephrology

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Renal malformations are a major cause of childhood renal failure. During the development of the kidney, ureteric bud (UB) branching morphogenesis is critical for normal nephrogenesis. These studies investigated whether renal UB branching morphogenesis is altered by a high ambient glucose environment and studied underlying mechanism(s). Kidney explants that were isolated from different periods of gestation (embryonic days 12 to 18) from Hoxb7-green fluorescence protein mice were cultured for 24 h in either normal D-glucose (5 mM) or high D-glucose (25 mM) medium with or without various inhibitors. Alterations in renal morphogenesis were assessed by fluorescence microscopy. Paired-homeobox 2 (Pax-2) gene expression was determined by real-time quantitative PCR, Western blotting, and immunohistology. The results revealed that high D-glucose (25 mM) specifically stimulates UB branching morphogenesis via Pax-2 gene expression, whereas other glucose analogs, such as D-mannitol, L-glucose, and 2-deoxy-Dglucose, had no effect. The stimulatory effect of high glucose on UB branching was blocked in the presence of catalase and inhibitors of NADPH oxidase, mitochondrial electron transport chain complex I, and Akt signaling. Moreover, in in vivo studies, it seems that high glucose induces, via Pax-2 (mainly localized in UB), acceleration of UB branching but not nephron formation. Taken together, these data demonstrate that high glucose alters UB branching morphogenesis. This occurs, at least in part, via reactive oxygen species generation, activation of Akt signaling, and upregulation of Pax-2 gene expression.

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Pax-2, kidney development, and oncogenesis

Cited by 42 publications

References 27 publications

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

Cell Biology of the Glomerular Podocyte

Reactive Oxygen Species in the Presence of High Glucose Alter Ureteric Bud Morphogenesis

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