Genetic Dissection of Increased Urinary Albumin Excretion in the Munich Wistar Fro[Combining Diaeresis]mter Rat

Abstract

Abstract. An elevated urinary albumin excretion (UAE) is a risk factor for the development of chronic nephropathy and for cardiovascular mortality. The Munich Wistar Frömter (MWF) rat represents a genetic model that develops spontaneously mild hypertension and a 142-fold increased UAE compared with normal Lewis rats at 14 wk of age. The genetic basis of UAE in male MWF was analyzed in relation to BP by using a quantitative trait (QTL) mapping strategy. F1-hybrids generated from a cross between MWF and Lewis rats showed normal UAE rates similar to Lewis. A backcross strategy including 213 animals was therefore used. To account for age-of-onset effects, UAE was determined in young backcross animals at 8 wk and in adult animals at 14 and 24 wk of age, respectively. Total genome scan analysis identified three QTL with significant linkage to UAE and one QTL with suggestive linkage to UAE. These loci showed no linkage to BP, and BP explained only 2% of the total variance of UAE. Homozygosity for the MWF allele accounted for a similar mean increase in UAE in adult backcross animals at each UAE QTL. When single gene effects were analyzed, only one UAE QTL led to a significant increase in UAE. Early onset of albuminuria and a considerable increase of UAE in adult animals required homozygosity at three loci at least. This study demonstrates the polygenetic recessive determination of increased UAE by a set of genes that are unlinked to BP.An elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy (1), and a moderate increase of UAE in the range of microalbuminuria represents an independent risk factor for cardiovascular events in patients with hypertension, diabetes or preexisting cardiovascular disease (2,3). With regard to the latter it is important to point out that microalbuminuria represents a quantitative clinical phenotype such as hypertension, which is arbitrarily defined on the basis of a quantitative cut-off value (1,4). Animal strains that display an increased UAE as an inherited trait represent an attractive substitute for the dissection of the polygenetic basis of UAE. Fully inbred animal models expressing a genetically determined disease avoid the problem of genetic heterogeneity, which in humans reduces statistical power to a degree that may preclude detection of individual genetic factors (5). In addition, animal experimentation allows a much more precise control of environmental factors compared with clinical studies. Most importantly, the ability to produce specific intercrosses between strains with low and high UAE rates represents a powerful experimental tool for carrying out genetic linkage analyses. The Munich Wistar Frömter (MWF) rat represents such an inbred genetic animal model that spontaneously develops an increased UAE (6). MWF animals develop also moderate spontaneous hypertension and exhibit a lower number of nephrons compared with other rat strains (7). Although both male and female MWF animals demonstrate a similar reduction in nephron number when compared w...

Quantitative Trait Loci for Glomerulosclerosis, Kidney Weight and Body Weight in the Focal Glomerulosclerosis Mouse Model

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Rf-2 Gene Modulates Proteinuria and Albuminuria Independently of Changes in Glomerular Permeability in the Fawn-Hooded Hypertensive Rat

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