Abstract
We previously confirmed in the Munich Wistar Frömter (MWF) rat a functional role of a major quantitative trait locus (QTL) on rat chromosome (RNO)6 for both albuminuria development and an inherited nephron deficit in the consomic strain MWF-6SHR. We addressed the question whether an inherited nephron deficit is linked to the genetic basis of albuminuria and whether common genetic factors are responsible for both phenotypes in this rat model. We generated congenic lines to dissect the RNO6-QTL using SHR rats with low albuminuria as a reference strain. Chromosomal fine mapping was performed by breeding of subcongenic lines, comparative genome analysis and physical mapping. The nephron number was determined by determination of the glomerular density in animals at 4 weeks of age; this method was validated by comparison with the absolute nephron numbers as determined by the physical fractionator method in parental strains. Phenotyping of the congenic lines covering the RNO6-QTL demonstrated that both the albuminuria and the nephron locus were subdivided into at least two different colocalized informative loci. One interval defined by the congenic lines MWF.SHR-(D6Rat1-D6Rat81) and MWF.SHR-(D6Rat1-D6Rat117) covers 2.1 Mb and contains 26 known genes. Exchange of this locus had a strong impact on albuminuria at 8 weeks of age resulting in a decrease from 18.1 to 5.0 mg/24 h (p<0.0001) between the congenic strains and affected also the glomerular density (184 vs. 223 /mm 3 , p=0.0004). The second interval flanked by the congenic lines MWF.SHR-(D6Rat1-D6Rat117) and MWF.SHR-(D6Rat1-D6Mgh4) encompasses 2.8 Mb and contains 49 known genes. This interval influenced also albuminuria (decrease from 5.0 to 1.5 mg/24h, p=0.0001) and glomerular density (223 vs. 243 /mm 3 , p=0.008). These findings support the genetic link between albuminuria and nephron deficit in this model and provide the basis for further functional and comparative genomic analysis to obtain new insights into this association.
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