Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic nephropathy is now the leading cause of end-stage renal diseases, and glomerular sclerotic injury is an initial event that provokes renal dysfunction during processes of diabetes-linked kidney disease. Growing evidence shows that transforming growth factor-beta 1 (TGF-beta 1) plays a key role in this process, especially in eliciting hypertrophy and matrix overaccumulation. Thus it is important to find a ligand system to antagonize the TGF-beta 1-mediated pathogenesis under high-glucose conditions. Herein, we provide evidence that hepatocyte growth factor (HGF) targets mesangial cells, suppresses TGF-beta 1 production, and minimizes glomerular sclerotic changes, using streptozotocin-induced diabetic mice. In our murine model, glomerular sclerogenesis (such as tuft area expansion and collagen deposition) progressed between 6 and 10 wk after the induction of hyperglycemia, during a natural course of diabetic disease. Glomerular HGF expression levels in the diabetic kidney transiently increased but then declined below a basal level, with manifestation of glomerular sclerogenesis. When anti-HGF IgG was injected into mice for 2 wk (i.e., from weeks 4 to 6 after onset of hyperglycemia), these glomerular changes were significantly aggravated. When recombinant HGF was injected into the mice for 4 wk (i.e., between 6 and 10 wk following streptozotocin treatment), the progression of glomerular hypertrophy and sclerosis was almost completely inhibited, even though glucose levels remained unchanged (>500 mg/dl). Even more important, HGF repressed TGF-beta 1 production in glomerular mesangial cells even under hyperglycemic conditions both in vitro and in vivo. Consequently, not only albuminuria but also tubulointerstitial fibrogenesis were attenuated by HGF. Overall, HGF therapy inhibited the onset of renal dysfunction in the diabetic mice. On the basis of these findings, we wish to emphasize that HGF plays physiological and therapeutic roles in blocking renal fibrogenesis during a course of diabetic nephropathy.
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PMID:Suppressions of chronic glomerular injuries and TGF-beta 1 production by HGF in attenuation of murine diabetic nephropathy. 1451 94

Islet transplantation for diabetes is limited by the availability of human islet donors. Hepatocyte growth factor (HGF) is a potent beta-cell mitogen and survival factor and improves islet transplant outcomes in a murine model. However, the murine model employs renal subcapsular transplant and immunodeficient mice, features not representative of human islet transplantation protocols. Therefore, we have developed a more rigorous, marginal-mass rat islet transplant model that more closely resembles human islet transplantation protocols: islet donors are allogeneic Lewis islets; recipients are normal Sprague Dawley rats; islets are delivered intraportally; and immunosuppression is accomplished using the same immunosuppressants employed by the Edmonton group. We demonstrate that 1) surprisingly, the Edmonton immunosuppression regimen induces marked insulin resistance and beta-cell toxicity in rats, 2) adenovirus does not adversely affect islet transplant outcomes, 3) the Edmonton immunosuppressants may delay or block rejection of adenovirally transduced islets, and more importantly, 4) pretransplant islet adenoviral gene therapy with HGF markedly improves islet transplant outcomes, 5) this enhanced function persists for months, and 6) HGF enhances islet function and survival even in the setting of immunosuppressant-induced insulin resistance and beta-cell toxicity. This approach may enhance islet transplantation outcomes in humans.
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PMID:Hepatocyte growth factor gene therapy for pancreatic islets in diabetes: reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation. 1473 50

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy.
Diabetes 2004 Apr
PMID:Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. 1504 30

It has been suggested that circulating concentrations of hepatocyte growth factor (HGF) are increased in individuals with vascular endothelial damage, such as in hypertensive patients and subjects with atherosclerosis. Because the influence of genetic variation of HGF has not been examined, we identified single nucleotide polymorphisms (SNPs) in the HGF gene, and investigated the association between these SNPs and blood pressure or carotid atherosclerosis in the Japanese general population. We identified 21 SNPs in the HGF gene by direct sequencing in a test population of 32 Japanese subjects. Among them, considering allele frequency and linkage disequilibrium, three SNPs, C-1652T in the promoter, T43839A in intron 8, and T44222C in intron 9, were genotyped in 2412 members of the Japanese general population randomly selected from the residents in Suita city. None of the three SNPs were significantly associated with blood pressure. After adjusting for age, smoking habits, consumption of alcohol, and the presence of diabetes mellitus and dyslipidemia, female subjects with the T allele of T43839A had more severe carotid atherosclerosis compared to individuals with the A allele. This study provides the first evidence that HGF may be a candidate susceptibility loci that affects the progression of atherosclerosis in Japanese subjects.
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PMID:Identification of 21 single nucleotide polymorphisms in human hepatocyte growth factor gene and association with blood pressure and carotid atherosclerosis in the Japanese population. 1506 6

During pancreatic development, neogenesis, and regeneration, stem cells might act as a central player to generate endocrine, acinar, and duct cells. Although these cells are well known as pancreatic stem cells (PSCs), indisputable proof of their existence has not been reported. Identification of phenotypic markers for PSCs leads to their prospective isolation and precise characterization to clear whether stem cells exist in the pancreas. By combining flow cytometry and clonal analysis, we show here that a possible pancreatic stem or progenitor cell candidate that resides in the developing and adult mouse pancreas expresses the receptor for the hepatocyte growth factor (HGF) c-Met, but does not express hematopoietic and vascular endothelial antigens such as CD45, TER119, c-Kit, and Flk-1. These cells formed clonal colonies in vitro and differentiated into multiple pancreatic lineage cells from single cells. Some of them could largely expand with self-renewing cell divisions in culture, and, following cell transplantation, they differentiated into pancreatic endocrine and acinar cells in vivo. Furthermore, they produced cells expressing multiple markers of nonpancreatic organs including liver, stomach, and intestine in vitro. Our data strongly suggest that c-Met/HGF signaling plays an important role in stem/progenitor cell function in both developing and adult pancreas. By using this antigen, PSCs could be isolated prospectively, enabling a detailed investigation of stem cell markers and application toward regenerative therapies for diabetes.
Diabetes 2004 Aug
PMID:Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. 1527 99

Peripheral neuropathy is common and ultimately accounts for significant morbidity in diabetes. Recently, several neurotrophic factors have been used to prevent progression of diabetic neuropathy. In this study, we gave repeated intramuscular injections of the human hepatocyte growth factor (HGF) gene percutaneously, using liposomes containing the hemagglutinating virus of Japan (HVJ), to examine therapeutic efficacy of nonviral gene transfer of HGF for experimental diabetic sensorimotor neuropathy in rats. Experimental diabetes induced by intraperitoneal injection of streptozotocin resulted in a marked tactile allodynia (but not in a thermal hyperalgesia), in a reduction of both the conduction velocity and the amplitude, and in a decreased laser Doppler flux of the nerve and the muscle at 6 weeks after the induction. All these changes were significantly reversed by repeated gene transfer of HGF. Furthermore, we analyzed the density of endoneurial capillaries and morphometrical changes of the nerve. The density of endoneurial capillaries, disclosing marked reduction in diabetic rats, was also reversed significantly by repeated gene transfer of HGF; however, no considerable differences were observed morphometrically in either myelinated or unmyelinated axons. These results suggest that nonviral HVJ liposome-mediated gene transfer of human HGF has potential for the safe effective treatment of diabetic sensorimotor neuropathy.
Diabetes 2005 Mar
PMID:Nonviral gene transfer of human hepatocyte growth factor improves streptozotocin-induced diabetic neuropathy in rats. 1573 64

Recent studies have demonstrated that the transplantation of bone marrow cells following diabetes induced by streptozotocin can support the recovery of pancreatic b-cell mass and a partial reversal of hyperglycemia. To address this issue, we examined whether the c-Met/hepatocyte growth factor (HGF) signaling pathway was involved in the recovery of b-cell injury after bone marrow transplantation (BMT). In this model, donor-derived bone marrow cells were positive for HGF immunoreactivity in the recipient spleen, liver, lung, and pancreas as well as in the host hepatocytes. Indeed, plasma HGF levels were maintained at a high value.The frequency of c-Met expression and its proliferative activity and differentiative response in the pancreatic ductal cells in the BMT group were greater than those in the PBS-treated group, resulting in an elevated number of endogenous insulin-producing cells. The induction of the c-Met/HGF signaling pathway following BMT promotes pancreatic regeneration in diabetic rats.
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PMID:Hepatocyte growth factor is constitutively produced by donor-derived bone marrow cells and promotes regeneration of pancreatic beta-cells. 1595 Jan 93

Overexpression of hepatocyte growth factor (HGF) in the beta-cell of transgenic mice enhances beta-cell proliferation, survival, and function. In the current studies, we have used conditional ablation of the c-met gene to uncover the physiological role of HGF in beta-cell growth and function. Mice in which c-met is inactivated in the beta-cell (MetCKO mice) display normal body weight, blood glucose, and plasma insulin compared with control littermates. In contrast, MetCKO mice displayed significantly diminished glucose tolerance and reduced plasma insulin after a glucose challenge in vivo. This impaired glucose tolerance in MetCKO mice was not caused by insulin resistance because sensitivity to exogenous insulin was similar in both groups. Importantly, in vitro glucose-stimulated insulin secretion in MetCKO islets was decreased by approximately 50% at high glucose concentrations compared with control islets. Furthermore, whereas insulin and glucokinase expression in MetCKO islets were normal, GLUT-2 expression was decreased by approximately 50%. These changes in beta-cell function in MetCKO mice were not accompanied by changes in total beta-cell mass, islet morphology, islet cell composition, and beta-cell proliferation. Interestingly, however, MetCKO mice display an increased number of small islets, mainly single and doublet beta-cells. We conclude that HGF/c-met signaling in the beta-cell is not essential for beta-cell growth, but it is essential for normal glucose-dependent insulin secretion.
Diabetes 2005 Jul
PMID:Targeted inactivation of hepatocyte growth factor receptor c-met in beta-cells leads to defective insulin secretion and GLUT-2 downregulation without alteration of beta-cell mass. 1598 10

The aim of the present study was to evaluate the vitreous levels of hepatocyte growth factor (HGF) in patients with proliferative diabetic retinopathy (PDR) and to investigate its relationship with vascular endothelial growth factor (VEGF) and retinopathy activity. In addition, the relationship between intravitreous HGF levels and the presence of epiretinal membranes (ERM), as well as the expression of c-Met in ERM were also investigated. In this case-control study, serum and vitreous samples as well as ERM specimens were obtained during vitrectomy from 28 diabetic patients with PDR and 30 non-diabetic control subjects. HGF and VEGF were determined by ELISA and c-Met expression by immunohistochemistry. Vitreal levels of both VEGF and HGF were higher in patients with PDR in comparison with the control group (p<0.0001). However, after correcting for total vitreous protein concentration, HGF (ng/mg of proteins) was lower in diabetic patients than in non-diabetic control subjects (p=0.02). No correlation was detected between the vitreal levels of HGF and VEGF. In addition, intravitreous VEGF but not HGF was found to be related to PDR activity. Both diabetic patients and non-diabetic patients in whom ERM had been excised presented higher HGF intravitreous levels. Finally, a significant expression of c-Met in ERM membranes were observed in both diabetic patients with PDR and in non-diabetic subjects. In conclusion, both HGF and VEGF increased, but were not related, in the vitreous fluid of diabetic patients with PDR. Our findings suggest that HGF is related to pathological conditions in which fibroproliferative processes or wound healing are involved rather than with angiogenesis itself.
Diabetes Res Clin Pract 2006 Jan
PMID:Intravitreous hepatocyte growth factor in patients with proliferative diabetic retinopathy: a case-control study. 1602 8

Nonenzymatic glycation of proteins to form advanced glycation end products (AGE) is implicated in diabetic complications, including nephropathy. It was shown recently that AGE bind to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeletal linker proteins in renal homogenates. Herein is reported the effects of AGE-BSA on ezrin-dependent LLC-PK1 kidney epithelial cellular functions: migration and hepatocyte growth factor (HGF)-induced tubulogenesis. LLC-PK1 cells were stably transfected with cDNA for ezrin sense, ezrin antisense, and N-ezrin. Transfection of LLC-PK1 cells with ezrin antisense and dominant negative N-ezrin decreased basal tubulogenesis and migration relative to vector-only transfection, establishing the ezrin dependency of these processes. AGE-BSA (20 or 40 microM) significantly decreased HGF-induced tubulogenesis and basal migration in two vector control lines relative to BSA-treated cells. However, AGE-BSA inhibition of both HGF-induced tubulogenesis and migration was overcome by overexpressing ezrin. These results demonstrate that the AGE-ezrin interaction significantly alters cellular function. These changes may be relevant to detrimental renal consequences as a result of diabetes.
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PMID:Advanced glycation end products inhibit tubulogenesis and migration of kidney epithelial cells in an ezrin-dependent manner. 1637 34


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