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Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism.

ABSTRACT: Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and activation of oxidative stress, proinflammatory cytokines, profibrotic growth factors, and the sterol regulatory element binding proteins, SREBP-1 and SREBP-2, that mediate increases in fatty acid and cholesterol synthesis. The purpose of the present study was to determine whether treatment of DIO mice with the vitamin D receptor (VDR) agonist doxercalciferol (1?-hydroxyvitamin D2) prevents renal disease. Our results indicate that treatment of DIO mice with the VDR agonist decreases proteinuria, podocyte injury, mesangial expansion, and extracellular matrix protein accumulation. The VDR agonist also decreases macrophage infiltration, oxidative stress, proinflammatory cytokines, and profibrotic growth factors. Furthermore, the VDR agonist also prevents the activation of the renin-angiotensin-aldosterone system including the angiotensin II type 1 receptor and the mineralocorticoid receptor. An additional novel finding of our study is that activation of VDR results in decreased accumulation of neutral lipids (triglycerides and cholesterol) and expression of adipophilin in the kidney by decreasing SREBP-1 and SREBP-2 expression and target enzymes that mediate fatty acid and cholesterol synthesis and increasing expression of the farnesoid X receptor. This study therefore demonstrates multiple novel effects of VDR activation in the kidney which prevent renal manifestations of DIO in the kidney.

SUBMITTER: Wang XX

PROVIDER: S-EPMC3064139 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism.

Wang Xiaoxin X XX Jiang Tao T Shen Yan Y Santamaria Hannah H Solis Nathaniel N Arbeeny Cynthia C Levi Moshe M

American journal of physiology. Renal physiology 20110105 3

Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and activation of oxidative stress, proinflammatory cytokines, profibrotic growth factors, and the sterol regulatory element binding proteins, SREBP-1 and SREBP-2, that mediate increases in fatty acid and cholesterol synthesis. The purpose of the present study was to determine whether treatment of DIO mice with the vitamin D receptor ...[more]

PMID: 21209008

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Project description:Fat greenling (Hexagrammos otakii) is a kind of economic fish that is widely consumed by human, and its intensive farming technology is making important progress. However, high-density farming may cause the occurrence of diseases in H. otakii. Cinnamaldehyde (CNE) is a new feed additive for aquatic animals and has a positive effect on disease resistance. In the study, dietary CNE was evaluated on the growth performance, digestion, immune response, and lipid metabolism of juvenile H. otakii (6.21 ± 0.19 g). Six experimental diets were formulated containing CNE at levels of 0, 200, 400, 600, 800, and 1000 mg/kg for 8 weeks. The percent weight gain (PWG), specific growth rate (SGR), survival (SR), and feeding rate (FR) were significantly increased by including CNE in fish diets regardless of the inclusion level (P < 0.05). The feed conversion ratio (FCR) was significantly decreased among the groups fed CNE supplemented diets (P < 0.05). A significant decrease in hepatosomatic index (HSI) was observed in fish fed 400 mg/kg-1000 mg/kg CNE compared to the control diet (P < 0.05). Fish-fed diets containing 400 mg/kg and 600 mg/kg CNE had a higher level of crude protein in muscles than the control diet (P < 0.05). Moreover, the activities of lipase (LPS) and pepsin (PEP) in the intestinal were markedly increased in juvenile H. otakii-fed dietary CNE (P < 0.05). Apparent digestibility coefficient (ADC) of dry matter, protein, and lipid was significantly increased with CNE supplement (P < 0.05). The activities of catalase (CAT) and acid phosphatase (ACP) in the liver were markedly enhanced by including CNE in juvenile H. otakii diets compared with the control (P < 0.05). The activities of superoxide dismutase (SOD) and alkaline phosphatase (AKP) in the liver were markedly enhanced in juvenile H. otakii treated with CNE supplements 400 mg/kg-1000 mg/kg (P < 0.05). Additionally, the levels of total protein (TP) in the serum were markedly increased by including CNE in juvenile H. otakii diets compared with the control (P < 0.05). In the CNE200, CNE400, and CNE600 groups, albumin (ALB) levels in the serum were markedly higher compared with that in the control (P < 0.05). In the CNE200 and CNE400 groups, the levels of immunoglobulin G (IgG) in the serum were significantly increased compared with that the control group (P < 0.05). The juvenile H. otakii-fed dietary CNE had lower triglycerides (TG) and total cholesterol (TCHO) levels in the serum than fish-fed CNE-free diets (P < 0.05). The gene expression of peroxisome proliferator-activated receptor alpha (PPAR-α), hormone-sensitive lipase (HSL), and carnitine O-palmitoyltransferase 1 (CPT1) in the liver was significantly increased by including CNE in fish diets regardless of the inclusion level (P < 0.05). However, fatty acid synthase (FAS), peroxisome proliferator-activated receptor gamma (PPAR-γ), and acetyl-CoA carboxylase alpha (ACCα) in the liver were markedly decreased with CNE supplements 400 mg/kg-1000 mg/kg (P < 0.05). The glucose-6-phosphate1-dehydrogenase (G6PD) gene expression levels in the liver were markedly decreased compared with the control (P < 0.05). The optimal supplementation level of CNE was shown by curve equation analysis to be 590.90 mg/kg.

Dataset Information

Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism.

Publications

Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism.

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