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1 Institute of Clinical Pharmacology and Toxicology
4 Department of Internal Medicine IV Nephrology, Universitätsklinikum Benjamin Franklin Hospital, Freie Universität Berlin, 12203 Berlin
2 Max-Delbrück Center for Molecular Medicine, Berlin Buch, 13125 Berlin, Germany
3 Department of Pathology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands
The aim of the study was to characterize the genetic basis for the early onset of increased urinary albumin excretion (UAE) observed in the salt-sensitive Dahl rat (SS). We first characterized blood pressures and UAE values in adult SS compared with the spontaneously hypertensive rat (SHR) strain. Blood pressure measurements by radiotelemetry at 14 wk demonstrated similar spontaneous hypertension in both strains on a low-sodium diet containing 0.2% NaCl by weight, whereas UAE was markedly increased in SS compared with SHR (253.07 ± 68.39 vs. 1.65 ± 1.09 mg/24 h, P < 0.0001). Analysis of UAE in young animals of both strains fed a low-sodium diet demonstrated that UAE is elevated in SS as early as 4 wk of age (P < 0.0001), when ultrastructural evaluation of glomeruli by electron microscopy appears still normal. At 8 wk SS demonstrated a 280-fold elevated UAE compared with SHR (P < 0.0001). Consequently, to identify quantitative trait loci (QTLs) contributing to salt-independent early manifestation of increased UAE in the SS rat, we performed genome-wide linkage and QTL mapping analysis in a young F2 population derived from the two contrasting strains. UAE was determined in 539 F2 animals at 8 wk. We identified seven suggestive or significant UAE QTLs on rat chromosomes (RNO) RNO2, RNO6, RNO8, RNO9, RNO10, RNO11, and RNO19, accounting together for 34% of the overall variance of UAE in this F2 population. Thus early onset albuminuria in the SS rat is under polygenetic influence and independent from salt loading.
genetics; linkage; quantitative trait loci
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