Hormones – Cytokines – Signaling
Kidney International (2003) 64, 1632–1642; doi:10.1046/j.1523-1755.2003.00263.x
Vitamin D3 up-regulated protein-1 regulates collagen expression in mesangial cells
Tsutomu Kobayashi, Sayuri Uehara, Takanori Ikeda, Hiraku Itadani and Hidehito Kotani
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Tsukuba, Ibaraki, Japan
Correspondence: Hidehito Kotani, Banyu Tsukuba Research Institute, Ibaraki 300-2611, Japan. E-mail: kotanihh@banyu.co.jp
Received 16 January 2003; Revised 16 June 2003; Accepted 26 June 2003.
Abstract
Vitamin D3 up-regulated protein-1 regulates collagen expression in mesangial cells.
Background
Hyperglycemia is a known risk factor in the pathogenesis of nephropathy, and collagen accumulation due to an increase reactive oxygen species (ROS) has been suspected to be one of the reasons for high glucose-mediated diseases. However, molecular mechanisms that connect glucose stimulation, oxidative stress, and collagen induction are unknown.
Methods
We examined global changes in gene expression patterns following high glucose stimulation by using DNA microarray technology in cultured human mesangial cells. The expression of vitamin D3 up-regulated protein-1 (VDUP-1), our candidate for the molecular mediator, was evaluated in the human mesangial cells, mouse mesangial cell line, and kidneys of diabetic mice by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Truncated VDUP-1 proteins were used to test the effects of VDUP-1 on the biosynthesis of collagen in mesangial cells.
Results
Expression of VDUP-1, which was reported as an inhibitor of thioredoxin, was induced rapidly and constantly after exposure to high concentrations of glucose upon analysis with DNA microarray. Overexpression of VDUP-1 gene in cultured mesangial cells resulted in type IV collagen 
1 chain (COL4A1) mRNA induction and accumulation of type IV collagen protein. However, induction of COL4A1 expression was abolished with a deletion mutant of VDUP-1, which lost thioredoxin-interacting domain. Also, streptozotocin-induced diabetic mice were shown to overexpress VDUP-1 as well as COL4A1.
Conclusion
VDUP-1 mediates collagen accumulation in mesangial cells and could be the molecular mediator/marker for fibrosis in diabetic nephropathy caused by chronic hyperglycemia such as diabetes.
Keywords:
diabetic nephropathy, hyperglycemia, DNA microarray, VDUP-1 collagen
