Abstract
The ICR-derived glomerulonephritis (ICGN) mouse is a chronic kidney disease (CKD) model that is characterized histologically by glomerulosclerosis, vascular sclerosis and tubulointerstitial fibrosis, and clinically by proteinuria and anemia, which are common symptoms and pathological changes associated with a variety of kidney diseases. Previously, we performed a quantitative trait locus (QTL) analysis to identify the causative genes for proteinuria in ICGN mice, and found a deletion mutation of the tensin 2 gene (Tns2nph, MGI no: 2447990). Interestingly, the congenic strain carrying the Tns2nph mutation on a C57BL/6J (B6) genetic background exhibited milder phenotypes than did ICGN mice, indicating the presence of several modifier genes controlling the disease phenotype. In this study, to identify the modifier/resistant loci for CKD progression in Tns2-deficient mice, we performed QTL analysis using backcross progenies from susceptible ICGN and resistant B6 mice. We identified a significant locus on chromosome (Chr) 2 (LOD = 5.36; 31 cM) and two suggestive loci on Chrs 10 (LOD = 2.27; 64 cM) and X (LOD = 2.65; 67 cM) with linkage to the severity of tubulointerstitial injury. One significant locus on Chr 13 (LOD = 3.49; approximately 14 cM) and one suggestive locus on Chr 2 (LOD = 2.41; 51 cM) were identified as QTLs for the severity of glomerulosclerosis. Suggestive locus in BUN was also detected in the same Chr 2 region (LOD = 2.34; 51 cM). A locus on Chr 2 (36 cM) was significantly linked with HGB (LOD = 4.47) and HCT (LOD = 3.58). Four novel epistatic loci controlling either HGB or tubulointerstitial injury were discovered. Further genetic analysis should lead to identification of CKD modifier gene(s), aiding early diagnosis and providing novel approaches to the discovery of drugs for the treatment and possible prevention of kidney disease.
Highlights
ICR-derived glomerulonephritis (ICGN) mice are an inbred strain that exhibit glomerulosclerosis characterized by marked glomerular hypertrophy, mesangial expansion, foot process effacement of podocytes and thickening of the glomerular basement membrane
Phenotypic Characterization of Tns2nph Backcross Mice To verify the effect of genetic background on susceptibility to chronic kidney disease (CKD) induced by Tns2nph, we produced a total of 246 (ICGN6B6) F16ICGN backcross mice and performed blood testing and histopathological analysis at the beginning of a genome-wide linkage analysis
Wide spectrums of blood urea nitrogen (BUN) and Hemoglobin concentration (HGB) were observed from the various degrees of Biomedical Innovation. C57BL/6J (B6) type to that of ICGN types (Fig. 1A)
Summary
ICR-derived glomerulonephritis (ICGN) mice are an inbred strain that exhibit glomerulosclerosis characterized by marked glomerular hypertrophy, mesangial expansion, foot process effacement of podocytes and thickening of the glomerular basement membrane. We performed a QTL analysis to isolate the causative genes for ICGN phenotypes, and identified a major QTL on chromosome (Chr) 15 that is identical to a single recessive locus causing albuminuria, and found a deletion mutation of the tensin 2 gene (Tns, known as Tenc). We performed a QTL analysis to isolate the causative genes for ICGN phenotypes, and identified a major QTL on chromosome (Chr) 15 that is identical to a single recessive locus causing albuminuria, and found a deletion mutation of the tensin 2 gene (Tns, known as Tenc1) This mutation (Tns2nph, MGI no: 2447990) leads to the loss of tensin 2 in podocytes, parietal epithelial cells and tubular epithelial cells [10]. Tns is thought to be a component of the actin cytoskeletal structures linking actin filaments with focal adhesions
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