Left‐right determination factor is down‐regulated in fibrotic renal tissue of human hydronephrosis

Yao, Yi; Zhang, Jie; Ye, Da-Fu; Tan, Daqing; Peng, Jianping; Xie, Mei; Li, Fang

doi:10.1111/j.1464-410x.2010.09520.x

Cited by 6 publications

(4 citation statements)

References 26 publications

(29 reference statements)

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“…Previous studies indicated that Lefty negatively modulates phosphorylation of receptor-activated Smads (R-Smads) and R-Smad/co-Smad copolymer in the TGF-β1/Smad pathway. 12 , 23 However, Lefty-1 treatment in our experiment failed to downregulate Smad2 and Smad4, the canonical TGF-β/Smads signaling components. Instead, we found that Lefty-1 significantly reduced the expression of Smad3 and enhanced BMP-5 expression.…”

Section: Discussionmentioning

confidence: 49%

Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells

Zhang¹,

Zhang²,

Xu³

et al. 2015

DDDT

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Fibroblast activation and proliferation are important for fibroblast–myofibroblast transdifferentiation, a crucial process in the pathological changes that define renal interstitial fibrosis. The left–right determination factor (Lefty) is an important cytokine of the transforming growth factor (TGF)-β family, with two variants, Lefty-1 and Lefty-2, in mice. Lefty has diverse functions, such as the regulation of embryonic development, the inhibition of TGF-β1 signaling, and the suppression of tumor activity. However, whether Lefty-1 influences fibroblast activation and proliferation, and consequently prevents fibroblast–myofibroblast transdifferentiation, remains unclear. This study aimed to investigate whether Lefty-1 can attenuate TGF-β1-induced fibroblast–myofibroblast transdifferentiation in normal rat kidney interstitial fibroblast cells (NRK-49F), as well as the mechanisms underlying any effects. Results showed that the typical fibroblast cell morphology of NRK-49F cells was altered after TGF-β1 treatment and that Lefty-1 significantly prevented this change in a dose-dependent manner. Further analyses demonstrated decreased proliferating cell nuclear antigen, cyclin D1, collagen I(A1), alpha-smooth muscle actin, and fibronectin expression. Lefty-1 further induced remarkable reductions in TGF-β1-induced Smad3 and mitogen-activated protein kinase-10/c-Jun N-terminal kinase (JNK-3) signaling, and enhanced expression of the antifibrotic factor bone morphogenetic protein (BMP)-5. However, without TGF-β1, Lefty-1 had no effect on Smad3, JNK-3, and BMP-5 activation and fibroblast–myofibroblast transdifferentiation. Taken together, these findings indicate that Lefty-1 can alleviate TGF-β1-mediated activation and the proliferation of fibroblasts. Furthermore, Lefty-1 may prevent fibroblast–myofibroblast transdifferentiation in part via modulations of Smad3, JNK-3, and BMP-5 activities in the TGF-β/BMP signaling pathway.

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Section: Discussionmentioning

confidence: 49%

Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells

Zhang¹,

Zhang²,

Xu³

et al. 2015

DDDT

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“…In fact, expressions of Bmp signaling genes (e.g., BMP2 , BMP7 and BMPRIA ) are reported to be decreased in the fibrotic renal tissue of human hydronephrosis [80]. The Bmp4 heterozygote mice display severe hydroureter and kidney hypoplasia with poorly differentiated ureteral smooth muscles [1], [81].…”

Section: Discussionmentioning

confidence: 99%

The Hedgehog Signal Induced Modulation of Bone Morphogenetic Protein Signaling: An Essential Signaling Relay for Urinary Tract Morphogenesis

et al. 2012

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BackgroundCongenital diseases of the urinary tract are frequently observed in infants. Such diseases present a number of developmental anomalies such as hydroureter and hydronephrosis. Although some genetically-modified mouse models of growth factor signaling genes reproduce urinary phenotypes, the pathogenic mechanisms remain obscure. Previous studies suggest that a portion of the cells in the external genitalia and bladder are derived from peri-cloacal mesenchymal cells that receive Hedgehog (Hh) signaling in the early developmental stages. We hypothesized that defects in such progenitor cells, which give rise to urinary tract tissues, may be a cause of such diseases.Methodology/Principal FindingsTo elucidate the pathogenic mechanisms of upper urinary tract malformations, we analyzed a series of Sonic hedgehog (Shh) deficient mice. Shh−/− displayed hydroureter and hydronephrosis phenotypes and reduced expression of several developmental markers. In addition, we suggested that Shh modulation at an early embryonic stage is responsible for such phenotypes by analyzing the Shh conditional mutants. Tissue contribution assays of Hh-responsive cells revealed that peri-cloacal mesenchymal cells, which received Hh signal secreted from cloacal epithelium, could contribute to the ureteral mesenchyme. Gain- and loss-of-functional mutants for Hh signaling revealed a correlation between Hh signaling and Bone morphogenetic protein (Bmp) signaling. Finally, a conditional ablation of Bmp receptor type IA (BmprIA) gene was examined in Hh-responsive cell lineages. This system thus made it possible to analyze the primary functions of the growth factor signaling relay. The defective Hh-to-Bmp signaling relay resulted in severe urinary tract phenotypes with a decrease in the number of Hh-responsive cells.Conclusions/SignificanceThis study identified the essential embryonic stages for the pathogenesis of urinary tract phenotypes. These results suggested that Hh-responsive mesenchymal Bmp signaling maintains the population of peri-cloacal mesenchyme cells, which is essential for the development of the ureter and the upper urinary tract.

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“…Although further study is still required, the present findings suggest that p23 overexpression can lead to hydronephrosis in anatomical obstruction and/or abnormal peristaltic movement of the ureter. In addition, fibrotic lesions associated with hydronephrosis are considered to be caused secondarily by the severe lesions seen in the kidney (Yao et al. 2010).…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice

Lee

Kim

Moon

et al. 2011

International Journal of Experimental Pathology

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p23 is a cochaperone of heat shock protein 90 and also interacts functionally with numerous steroid receptors and kinases. However, the in vivo roles of p23 remain unclear. To explore its in vivo function, we generated the transgenic (TG) mice ubiquitously overexpressing p23. The p23 TG mice spontaneously developed kidney abnormalities closely resembling human hydronephrosis. Consistently, kidney functions deteriorate significantly in the p23 TG mice compared to their wild-type (WT) littermates. Furthermore, the expression of target genes for aryl hydrocarbon receptor (AhR), such as cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (Cyp1B1), were induced in the kidneys of the p23 TG mice. These results indicate that the overexpression of p23 contributes to the development of hydronephrosis through the upregulation of the AhR pathway in vivo.

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Left‐right determination factor is down‐regulated in fibrotic renal tissue of human hydronephrosis

Cited by 6 publications

References 26 publications

Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells

Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells

The Hedgehog Signal Induced Modulation of Bone Morphogenetic Protein Signaling: An Essential Signaling Relay for Urinary Tract Morphogenesis

Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice

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Left‐right determination factor is down‐regulated in fibrotic renal tissue of human hydronephrosis

Cited by 6 publications

References 26 publications

Lefty-1 alleviates TGF-&beta;1-induced fibroblast&ndash;myofibroblast transdifferentiation in NRK-49F cells

Lefty-1 alleviates TGF-&beta;1-induced fibroblast&ndash;myofibroblast transdifferentiation in NRK-49F cells

The Hedgehog Signal Induced Modulation of Bone Morphogenetic Protein Signaling: An Essential Signaling Relay for Urinary Tract Morphogenesis

Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice

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Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells

Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells