Mediation of renal cyst formation by hepatocyte growth factor

Horie, Shigeo; Kano, Mayuko; Kawabe, Kazuki; Mikami, Yuji; Okubo, Ayako; Nutahara, Kikuo; Higashihara, Eiji

doi:10.1016/s0140-6736(94)92344-2

Cited by 62 publications

(30 citation statements)

References 5 publications

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“…In the present study, we have shown that in Pkd1 -/-cells, there is a hyperactivation of c-Met signaling, due to a failure to ubiquitinate c-Met following stimulation with HGF. A role for HGF signaling in cystic disease was suggested by previous studies in which transgenic mice overexpressing HGF developed prominent tubular cysts in their kidneys (33) and elevated levels of HGF have been detected in cyst fluid from PKD patients (6). Normally, activation of c-Met leads to recruitment and phosphorylation of c-Cbl, an E3 ubiquitin ligase for c-Met.…”

Section: Discussionmentioning

confidence: 94%

“…A role for c-Met in branching morphogenesis within the developing kidney has long been suggested because of the ability of HGF to stimulate the formation of branched tubules by MDCK cells in 3D collagen gels (15,16). A role for HGF and c-Met in cystic kidney disease has also been suggested by observations that both HGF and c-Met are overexpressed by cyst-lining cells in kidneys from individuals with PKD or acquired cystic disease (6,17).…”

Section: Introductionmentioning

confidence: 99%

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Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Qin¹,

Taglienti²,

Nauli³

et al. 2010

J. Clin. Invest.

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Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B-lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with α 3 β 1 integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Qin¹,

Taglienti²,

Nauli³

et al. 2010

J. Clin. Invest.

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“…Tumour markers are believed to be released from lung epithelial cells and secretory IgA is produced by the epithelial cells of the respiratory tract [21]. MUKAE et al [22] showed that CA19-9 levels are high in serum and BALF of patients with IPF, PF-CVD, bronchiectasis, and diffuse panbronchiolitis.…”

Section: Resultsmentioning

confidence: 99%

Neutrophil elastase: alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis

Yamanouchi¹,

Fujita²,

Hojo³

et al. 1998

Eur Respir J

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It was hypothesized that neutrophil elastase released from activated neutrophils may play an important role in the pathogenesis of pulmonary fibrosis. In the present study, we measured the neutrophil elastase:alpha-1-proteinase inhibitor complex (E-PI) in serum and bronchoalveolar lavage fluid (BALF) in 26 patients with pulmonary fibrosis and evaluated the correlation between E-PI levels and several parameters. E-PI levels in serum of patients with pulmonary fibrosis (635.8+/-112.0 ng.mL(-1)) were significantly elevated compared to normal nonsmokers (122.0+/-4.0 ng.mL(-1)) as well as normal smokers (132.8+/-8.4 ng.mL(-1)) (p<0.01). E-PI levels in serum significantly correlated with hepatocyte growth factor (HGF) levels in serum, C-reactive protein (CRP), and negatively correlated with arterial oxygen tension (Pa,O2), and arterial carbon dioxide tension (Pa,CO2). E-PI/albumin levels in BALF significantly correlated with HGF/albumin levels in BALF, lactate dehydrogenase (LDH)/albumin in BALF, total number of inflammatory cells (alveolar macrophages and neutrophils) in BALF, and several markers derived from epithelial cells in BALF. Our data demonstrated: 1) neutrophil elastase:alpha-1-proteinase inhibitor complex in serum increased in patients with pulmonary fibrosis; and 2) neutrophil elastase:alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid correlated with clinical parameters in pulmonary fibrosis. These results suggest that neutrophil elastase may play a significant role in the process of lung injury in pulmonary fibrosis.

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“…Therefore, such antibodies will likely be ineffective if their targets are present on the apical surface of cyst-lining cells or within the cyst fluid. Several growth factors have been identified previously in renal cyst fluid and implicated in driving cyst growth, such as EGF, hepatocyte growth factor, and TNF-␣ (7)(8)(9). Similarly, our previous results indicated that STAT6 is aberrantly activated in cyst-lining cells because of auto/paracrine stimulation of the IL4/13 receptor by IL13 present in cyst fluid (12).…”

Section: Discussionmentioning

confidence: 99%

Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease

Olsan

Matsushita

Rezaei

et al. 2015

Journal of Biological Chemistry

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Mediation of renal cyst formation by hepatocyte growth factor

Cited by 62 publications

References 5 publications

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

Neutrophil elastase: alpha-1-proteinase inhibitor complex in serum and bronchoalveolar lavage fluid in patients with pulmonary fibrosis

Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease

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