FAR2
Fatty acyl-CoA reductase 2 (EC 1.2.1.84) (Male sterility domain-containing protein 1) [MLSTD1]
Publications[править]
Mesangial matrix expansion is an important process in the initiation of chronic kidney disease, yet the genetic factors driving its development are unknown. Our previous studies have implicated Far2 as a candidate gene associated with differences in mesangial matrix expansion between mouse inbred strains. Consistent with the hypothesis that increased expression of Far2 leads to mesangial matrix expansion through increased production of platelet-activating factor precursors, we show that FAR2 is capable of mediating de novo platelet-activating factor synthesis in vitro and driven by the transcription factor NKX3.2. We demonstrate that knockdown of Far2 in mice delays the progression of mesangial matrix expansion with at least six months (equivalent to ~15 yr in human). Furthermore, we show that increased FAR2 expression in human patients is associated with diabetic nephropathy, lupus nephritis, and IgA nephropathy. Taken together, these results highlight FAR2's role in the development of mesangial matrix expansion and chronic kidney disease.
MeSH Terms
- Adult
- Aged
- Aldehyde Oxidoreductases
- Animals
- Diabetic Nephropathies
- Female
- Glomerular Mesangium
- Homeodomain Proteins
- Humans
- Male
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Transcription Factors
- Young Adult
Keywords
- aging
- kidney
- mesangial matrix
- mouse
Aging of the kidney is associated with renal damage, in particular mesangial matrix expansion (MME). Identifying the genes involved in this process will help to unravel the mechanisms of aging and aid in the design of novel therapeutic modalities aimed at prevention and regression. In this study, structural changes in glomeruli of 24 inbred mouse strains were characterized in male mice at 6, 12, and 20 months of age. Haplotype association mapping was used to determine genetic loci associated with the presence of MME at 20 months. This analysis identified a significant association with a 200-kb haplotype block on chromosome 6 containing Far2. Sequencing revealed that mouse strains with MME contain a 9-bp sequence in the 5' untranslated region of Far2 that is absent in most of the strains without MME. Real-time PCR showed a two-fold increase in the expression of Far2 in the kidneys of strains with the insert, and subsequent experiments performed in vitro with luciferase reporter vectors showed that this sequence difference causes differential expression of Far2. Overexpression of Far2 in a mouse mesangial cell line induced upregulation of platelet activating factor and the fibrotic marker TGF-β. This upregulation of MME-promoting factors may result, in part, from the FAR2-catalyzed reduction of fatty acyl-coenzyme A to fatty alcohols, which are possible precursors of platelet activating factor. Overall, these data suggest the identification of a novel pathway involved in renal aging that may yield therapeutic targets for reducing MME.
MeSH Terms
- Aging
- Aldehyde Oxidoreductases
- Animals
- Chromosome Mapping
- Haplotypes
- Kidney Glomerulus
- Male
- Mesangial Cells
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Inbred MRL lpr
- Mice, Inbred NOD
- Species Specificity