Genetic Analysis of Mesangial Matrix Expansion in Aging Mice and Identification of Far2 as a Candidate Gene

Abstract

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 59 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-b. 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.

Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma

“…MME , a downregulated gene in the present study, encodes a glycoprotein identified in a variety of normal and malignant tissues. This glycoprotein is particularly abundant in kidney, where it is present on the brush border of proximal tubules and on glomerular epithelium ( 32 ). Amălinei et al ( 33 ) reported that the generation of angiostatin induced by MME was responsible for the prevention of tumor growth.…”

Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

“…MME was involved in kidney development, and it is abundantly expressed in the kidney[ 22 ], particularly in podocytes[ 23 ]. Expression of MME at mRNA levels was significantly down-regulated in kidneys of patients with diabetic nephropathy (DN) [ 24 ].…”

A roadmap for the genetic analysis of renal aging

“…Two of the nine loci were associated with diabetic nephropathy in humans. The haplotype association mapping technique used on histological phenotypes in the same inbred strains identified Far2 as being associated with mesangial matrix expansion (MME) in aging mice (Noordmans et al ., 2013 ). MME is a characteristic of glomerular aging and a precursor of glomerulosclerosis.…”

“…Far2 encodes the protein fatty acyl-coenzyme A reductase 2, which catalyzes the reduction of fatty acyl-CoA to fatty alcohols, a precursor of platelet-activating factor (PAF). Both in vivo and in vitro , this insertion was associated with increased expression of Far2 , leading to upregulation of PAF and TGFβ, which are involved in the pathogenesis of sclerosis (Noordmans et al ., 2013 ). There were some strains in this study with the Far2 insertion but in which MME was not observed suggesting additional genes involved in this phenotype.…”