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Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.

ABSTRACT: BACKGROUND:?Human eNOS (NOS3) polymorphisms that lower its expression are associated with advanced diabetic nephropathy (DN), and the lack of eNOS accelerates DN in diabetic mice. Diabetes is associated with fibrin deposition. Lack of nitric oxide and fatty acids stimulates the NF-kB pathway, which increases tissue factor (TF). OBJECTIVES:?To test the hypothesis that TF contributes to the severity of DN in the diabetic eNOS(-/-) mice fed a high-fat diet (HF). METHODS:?We made eNOS(-/-) and wild-type mice diabetic with streptozotocin. Half of them were placed on HF. RESULTS:?Blood glucose levels were not affected by either the diet or eNOS genotype. Lack of eNOS in the diabetic mice increased urinary albumin excretion, glomerulosclerosis, interstitial fibrosis, and glomerular basement membrane thickness. HF by itself did not affect DN in the wild-type mice, but significantly enhanced DN in eNOS(-/-) mice. More than half of diabetic eNOS(-/-) mice on HF died prematurely with signs of thrombotic complications. Diabetic kidneys contained fibrin and TF, and their levels were increased by the lack of eNOS and by HF in an additive fashion. The HF diet increased the kidney expression of inflammatory genes. The increase in TF preceded DN, and administration of an anti-mouse TF antibody to diabetic mice reduced the expression of inflammatory genes. CONCLUSION:?Together, these data indicate a causal link between TF and the exacerbation of DN in eNOS(-/-) mice. The condition is significantly worsened by enhanced inflammatory responses to an HF diet via TF.

SUBMITTER: Li F

PROVIDER: S-EPMC5744483 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.

Li F F Wang C-H CH Wang J-G JG Thai T T Boysen G G Xu L L Turner A L AL Wolberg A S AS Mackman N N Maeda N N Takahashi N N

Journal of thrombosis and haemostasis : JTH 20101001 10

<h4>Background</h4> Human eNOS (NOS3) polymorphisms that lower its expression are associated with advanced diabetic nephropathy (DN), and the lack of eNOS accelerates DN in diabetic mice. Diabetes is associated with fibrin deposition. Lack of nitric oxide and fatty acids stimulates the NF-kB pathway, which increases tissue factor (TF).<h4>Objectives</h4> To test the hypothesis that TF contributes to the severity of DN in the diabetic eNOS(-/-) mice fed a high-fat diet (HF).<h4>Methods</h4> We ma ...[more]

PMID: 20626618

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Project description:BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, although its pathogenesis remains to be elucidated. A recent study revealed that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver expressed on the bile canalicular membrane, is an exacerbation factor of NAFLD. Indeed, transgenic mice with hepatic expression of human NPC1L1 under a liver-specific promoter (L1-Tg mice) developed steatosis with a high-fat diet (HFD) containing cholesterol within a few weeks. However, the mechanism underlying diet-induced hepatic NPC1L1-mediated lipid accumulation is poorly defined. METHODS:To achieve a deeper understanding of steatosis development in L1-Tg mice, the biochemical features of hepatic NPC1L1-mediated steatosis were investigated. Hemizygous L1-Tg mice and wild-type littermate controls fed a HFD or control-fat diet were used. At the indicated time points, the livers were evaluated for cholesterol and triglyceride (TG) contents as well as mRNA levels of hepatic genes involved in the maintenance of lipid homeostasis. The hepatic ability to secrete very low-density lipoprotein (VLDL)-TG was also investigated. RESULTS:Unlike the livers of wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice displayed time-dependent changes that indicated steatosis formation. In steatosis, there were three different stages of development: mild accumulation of hepatic cholesterol and TG (early stage), acceleration of hepatic TG accumulation (middle stage), and further accumulation of hepatic cholesterol (late stage). In the early stage, between WT and L1-Tg mice fed a HFD for 2?weeks, there were no significant differences in the hepatic expression of Ppar?, Acox1, Fat/Cd36, Srebf1, and Srebf2; however, the hepatic ability to secrete VLDL-TG decreased in L1-Tg mice (P?<?0.05). Furthermore, this decrease was completely prevented by administration of ezetimibe, an NPC1L1-selective inhibitor. CONCLUSION:Hepatic NPC1L1 exacerbates diet-induced steatosis, which was accompanied by decreased hepatic ability of VLDL-TG secretion. The obtained results provide a deeper understanding of L1-Tg mice as a promising NAFLD animal model that is able to re-absorb biliary-secreted cholesterol similar to humans. Furthermore, this work supports further studies of the pathophysiological impact of re-absorbed biliary cholesterol on the regulation of hepatic lipid homeostasis.

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Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.

Publications

Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.

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