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1 Institute of Clinical Pharmacology and Toxicology, Freie Universitaet Berlin, Berlin, Germany
2 Max-Delbrueck Center for Molecular Medicine, Berlin, Germany
3 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
4 Institute of Clinical Pharmacology and Toxicology, Freie Universitaet Berlin, Berlin, Germany; Internal Medicine IV Nephrology, Freie Universitaet Berlin, Berlin, Germany
* To whom correspondence should be addressed. E-mail: kreutz{at}medizin.fu-berlin.de.
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 in adult SS in comparison to 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, while UAE was markedly increased in SS compared to 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 to 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 7 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.
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