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BASIC SCIENCE |
*Institute of Clinical Pharmacology and Toxicology and Department of Nephrology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany; and Institute for Arteriosclerosis Research, Westfälische-Wilhelms-Universität Münster, Münster, Germany
Correspondence to Dr. Reinhold Kreutz, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. Phone: +49-30-8445-2280; Fax: +49-30-8445-4482; E-mail: kreutz{at}medizin.fu-berlin.de
ABSTRACT. The development of renal interstitial fibrosis (RIF) represents an important step in the progression of chronic proteinuric nephropathies. The Munich Wistar Frömter (MWF) rat represents a valuable model to study the progression in proteinuric renal disease. MWF animals demonstrate a significant increase of urinary albumin excretion (UAE) and RIF compared with the spontaneously hypertensive rat (SHR) with low UAE. The aim of this study was to analyze the genetic basis and the relation between UAE and RIF by genetic linkage and quantitative trait loci (QTL) mapping analysis. The authors generated a backcross population between MWF and SHR including 215 male animals. UAE was determined in young backcross animals at 8 wk, and at 14 and 24 wk of age, respectively. RIF was evaluated by Sirius red staining of kidney sections and quantified by computer-assisted image analysis at 24 wk. Total genome scan analysis identified in total eight QTL linked to UAE and a major locus on chromosome 6. At this locus, homozygosity for the MWF allele exhibited a strong effect on UAE levels (threefold elevation) and displayed significant linkage already at 8 wk (logarithm of odds [LOD] = 4.3) with increasing significance at 14 and 24 wk (LOD = 7.8 and 10.1, respectively). In addition, this was the only QTL that was linked to the amount of RIF (P = 0.0009, LOD = 2.4). These data establish a genetic link between early onset albuminuria and progression of RIF at the QTL on RNO6. This study demonstrates the power of genetic linkage analysis for the dissection of physiologic pathways involved in renal disease progression.
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