Immunohistochemical Localization of Hepatocyte Growth Factor Protein in Pancreas Islet A‐Cells of Man and Rats

Tsuda, Hiroyuki; Iwase, Teruhiko; Matsumoto, Kazuyuki; Ito, Mitsuya; Hirono, Iwao; Nishida, Yoshihisa; Yamamoto, Masami; Tatematsu, Masae; Matsumoto, Kunio; Nakamura, Toshikazu

doi:10.1111/j.1349-7006.1992.tb02756.x

Cited by 36 publications

(21 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These in vivo results extend previous in vitro findings suggesting that HGF is one of the most potent mitogens and insulinotropic agents for beta cells (14,19,20). Since HGF is produced in the pancreas (12)(13)(14)(15)(16)(17) and the c-Met receptor is localized in the islet beta cells (14), it seems likely that HGF may play a paracrine and/or autocrine physiological role in the growth and development of the pancreatic islet.…”

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Garcı́a-Ocaña¹,

Takane²,

Syed³

et al. 2000

Journal of Biological Chemistry

227

211

View full text Add to dashboard Cite

Hepatocyte growth factor (HGF) is produced in pancreatic mesenchyme-derived cells and in islet cells. In vitro, HGF increases the insulin content and proliferation of islets. To study the role of HGF in the islet in vivo, we have developed three lines of transgenic mice overexpressing mHGF using the rat insulin II promoter (RIP). Each RIP-HGF transgenic line displays clear expression of HGF mRNA and protein in the islet. RIPmHGF mice are relatively hypoglycemic in post-prandial and fasting states compared with their normal littermates. They display inappropriate insulin production, striking overexpression of insulin mRNA in the islet, and a 2-fold increase in the insulin content in islet extracts. Importantly, beta cell replication rates in vivo are two to three times higher in RIP-HGF mice. This increase in proliferation results in a 2-3-fold increase in islet mass. Moreover, the islet number per pancreatic area was also increased by approximately 50%. Finally, RIP-mHGF mice show a dramatically attenuated response to the diabetogenic effects of streptozotocin. We conclude that the overexpression of HGF in the islet increases beta cell proliferation, islet number, beta cell mass, and total insulin production in vivo. These combined effects result in mild hypoglycemia and resistance to the diabetogenic effects of streptozotocin. Hepatocyte growth factor (HGF)1 is a mesenchyme-derived protein originally identified as a circulating factor implicated in liver regeneration after hepatic injury or hepatectomy (1-3). It is now recognized that HGF also exhibits its mitogenic, motogenic, and morphogenic activities in a wide variety of cells (4, 5). The active form of HGF is a disulfide-linked heterodimeric protein, which is composed of a 69-kDa ␣-chain and a 34-kDa ␤-chain, containing four kringle domains and a serine protease-like domain, respectively. Active HGF derives from an inactive single chain precursor that is processed and activated by proteolysis. Four proteases have been reported to date to activate HGF in vitro, including blood coagulation factor XIIa, urokinase, tissue-type plasminogen activator, and a serumderived serine protease named HGF activator (6 -9). HGF is primarily a paracrine factor produced by mesenchymal cells that acts on epithelial cells through a membrane-spanning tyrosine kinase receptor, the protein product of the proto-oncogene, c-met (5, 10, 11). The receptor, like the ligand, has a widespread distribution.Messenger RNAs encoding HGF and the HGF receptor, cmet, are highly expressed during the early development of the pancreas, and then maintained at a low level during puberty and adult life (12)(13)(14). HGF has been detected immunohistochemically in the exocrine portion of rabbit pancreas, and in rat and human pancreatic islet cells (15-17). Tissue-type plasminogen activator has been detected in the rat endocrine pancreas, preferentially in somatostatin cells (18). In addition, confocal immunofluorescent studies have preferentially colocalized the c-Met receptor protein to insulin-conta...

show abstract

Section: Discussionsupporting

confidence: 85%

“…HGF has been detected immunohistochemically in the exocrine portion of rabbit pancreas, and in rat and human pancreatic islet cells (15)(16)(17). Tissue-type plasminogen activator has been detected in the rat endocrine pancreas, preferentially in somatostatin cells (18).…”

mentioning

confidence: 99%

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Garcı́a-Ocaña¹,

Takane²,

Syed³

et al. 2000

Journal of Biological Chemistry

227

211

View full text Add to dashboard Cite

show abstract

“…Tissue specimens (6 µm thick) from the mid-section of the blood vessels were sectioned at 60 µm intervals along the vessel in a proximal to distal fashion. Sections were stained using an enzyme immunohistochemical kit (Histostain-SP kit; Zymed Lab., Inc., South San Francisco, CA, USA) with rabbit polyclonal antibody against rat HGF (1:1000 dilution; Tokushu Meneki Institute (Tsuda et al 1992)) and rat c-met (1:1000 dilution; Tokushu Meneki Institute ), which was tested for cross-reactivity with rat HGF .…”

Section: Immunohistochemical Analysesmentioning

confidence: 99%

Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administration of prostaglandin I2 analogue

Matsumoto

Morishita

Tomita³

et al. 2002

Journal of Endocrinology

View full text Add to dashboard Cite

We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high -glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I 2 (PGI 2 ) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI 2 analogue in the regulation of the local HGF system using DM rats.A PGI 2 analogue (beraprost sodium; 300 and 600 µg/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0·01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI 2 treatment in a dose-dependent manner (P<0·01), whereas N(omega)-nitro--arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI 2 as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI 2 treatment.Overall, this study demonstrated that treatment with a PGI 2 analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI 2 analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.

show abstract

“…Factors that could increase beta cell growth, survival or function are therefore urgently needed. In recent years, candidate gene studies have demonstrated that islets express and secrete factors in addition to the classical hormones, including multiple cytokines, neuropeptides and growth factors [2,3]. In parallel, targeted studies have revealed growth factors that promote islet cell survival when overexpressed or added exogenously.…”

Section: Introductionmentioning

confidence: 99%

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis Adult pancreatic islets contain multiple cell types that produce and secrete well characterised hormones, including insulin, glucagon and somatostatin. Although it is increasingly apparent that islets release and respond to more secreted factors than previously thought, systematic analyses are lacking. We therefore sought to identify potential autocrine and/or paracrine islet growth factor loops, and to characterise the function of the netrin family of islet-secreted factors and their receptors, which have been previously unreported in adult islets. Methods Gene expression databases, islet-specific tag sequencing libraries and microarray datasets of FACS purified beta cells were used to compile a list of secreted factors and receptors present in mouse or human islets. Netrins and their receptors were further assessed using RT-PCR, Western blot analysis and immunofluorescence staining. The roles of netrin-1 and netrin-4 in beta cell function, apoptosis and proliferation were also examined. Results We identified 233 secreted factors and 234 secreted factor receptors in islets. The presence of netrins and their receptors was further confirmed. Downregulation of caspase-3 activation was observed when MIN6 cells were exposed to exogenous netrin-1 and netrin-4 under hyperglycaemic conditions. Reduction in caspase-3 cleavage was linked to the decrease in dependence receptors, neogenin and unc-5 homologue A, as well as the activation of Akt and extracellular signal-regulated protein kinase (ERK) signalling. Conclusions/interpretation Our results highlight the large number of potential islet growth factors and point to a context-dependent pro-survival role for netrins in adult beta cells. Since diabetes results from a deficiency in functional beta cell mass, these studies are important steps towards developing novel therapies to improve beta cell survival.

show abstract

Immunohistochemical Localization of Hepatocyte Growth Factor Protein in Pancreas Islet A‐Cells of Man and Rats

Cited by 36 publications

References 29 publications

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administration of prostaglandin I2 analogue

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

Contact Info

Product

Resources

About