Hepatocyte growth factor is elevated in amniotic fluid from obese women and regulates placental glucose and fatty acid metabolism

Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte‐specific glucocorticoid receptor knockout (GR PKO ) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GR PKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor‐βR1 and β‐catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin‐positive cells were found in the kidneys of diabetic GR PKO mice. Podocytes isolated from diabetic GR PKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GR PKO mice. The glomerular endothelium of diabetic GR PKO mice demonstrated the features of endothelial‐to‐mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α‐smooth muscle actin, transforming growth factor‐βR1 and β‐catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte–endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

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Second trimester amniotic fluid level of hepatocyte growth factor is not a predictor of untoward pregnancy outcome

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)86601-4 ◽

1998 ◽

Vol 5 (1) ◽

pp. 167A-167A

Author(s):

A GHIDINI ◽

C SPONG ◽

C LOUCKS ◽

G DILDV ◽

M VARRER ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Amniotic Fluid ◽

Pregnancy Outcome ◽

Second Trimester ◽

Fluid Level ◽

Hepatocyte Growth

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Human Amniotic Fluid Motogenic Activity for Fetal Alveolar Type II Cells by Way of Hepatocyte Growth Factor

Obstetrics and Gynecology ◽

10.1016/s0029-7844(97)00083-5 ◽

1997 ◽

Vol 89 (5) ◽

pp. 729-733 ◽

Cited By ~ 6

Author(s):

A Itakura

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Amniotic Fluid ◽

Alveolar Type ◽

Type Ii Cells ◽

Type Ii ◽

Human Amniotic Fluid ◽

Alveolar Type Ii Cells ◽

Hepatocyte Growth

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The Concentration of Hepatocyte Growth Factor (HGF) in Human Amniotic Fluid at Second Trimester: Relation to Fetal Birth Weight

Hormone and Metabolic Research ◽

10.1055/s-2007-979973 ◽

1995 ◽

Vol 27 (07) ◽

pp. 335-338 ◽

Cited By ~ 12

Author(s):

O. Kurauchi ◽

A. Itakura ◽

H. Ando ◽

N. Kuno ◽

S. Mizutani ◽

...

Keyword(s):

Birth Weight ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Amniotic Fluid ◽

Second Trimester ◽

Human Amniotic Fluid ◽

Fetal Birth Weight ◽

Hepatocyte Growth

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Novel Proapoptotic Effect of Hepatocyte Growth Factor: Synergy with Palmitate to Cause Pancreatic β-Cell Apoptosis

Endocrinology ◽

10.1210/en.2009-0975 ◽

2010 ◽

Vol 151 (4) ◽

pp. 1487-1498 ◽

Cited By ~ 12

Author(s):

José A. González-Pertusa ◽

John Dubé ◽

Shelley R. Valle ◽

Taylor C. Rosa ◽

Karen K. Takane ◽

...

Keyword(s):

Fatty Acid ◽

Growth Factor ◽

Transgenic Mice ◽

Hepatocyte Growth Factor ◽

Transgenic Mouse ◽

Glucose Homeostasis ◽

Cell Apoptosis ◽

Β Cells ◽

Β Cell ◽

Hepatocyte Growth

Increasing evidence suggests that elevation of plasma fatty acids that often accompanies insulin resistance contributes to β-cell insufficiency in obesity-related type 2 diabetes. Circulating levels of hepatocyte growth factor (HGF) are increased in humans with metabolic syndrome and obesity. HGF is known to protect β-cells against streptozotocin and during islet engraftment. However, whether HGF is a β-cell prosurvival factor in situations of excessive lipid supply has not been deciphered. Mice overexpressing HGF in the β-cell [rat insulin type II promoter (RIP)-HGF transgenic mice] fed with standard chow display improved glucose homeostasis and increased β-cell mass and proliferation compared with normal littermates. However, after 15 wk of high-fat feeding, glucose homeostasis and β-cell expansion and proliferation are indistinguishable between normal and transgenic mice. Interestingly, RIP-HGF transgenic mouse β-cells and normal β-cells treated with HGF display increased sensitivity to palmitate-mediated apoptosis in vitro. Palmitate completely eliminates Akt and Bad phosphorylation in RIP-HGF transgenic mouse islets. HGF-overexpressing islets also show significantly decreased AMP-activated protein kinase-α and acetyl-coenzyme A carboxylase phosphorylation, diminished fatty acid oxidation, increased serine palmitoyltransferase expression, and enhanced ceramide formation compared with normal islets. Importantly, human islets overexpressing HGF also display increased β-cell apoptosis in the presence of palmitate. Treatment of both mouse and human islet cells with the de novo ceramide synthesis inhibitors myriocin and fumonisin B1 abrogates β-cell apoptosis induced by HGF and palmitate. Collectively, these studies indicate that HGF can be detrimental for β-cell survival in an environment with excessive fatty acid supply.

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