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1 Laboratory for Molecular Medicine and Israeli Rat Genome Center, Faculty of Health Sciences, Ben-Gurion University, Barzilai Medical Center Campus, Ashkelon 78306
2 Department of Pathology, Shaare Zedeq Medical Center, Jerusalem 91031, Israel
In search of an experimental model that would simulate the association between proteinuria and salt sensitivity in humans, we studied protein excretion in the Sabra rat model of salt susceptibility. Monthly measurements of urinary protein excretion in animals fed standard rat chow revealed that normotensive salt-sensitive SBH/y developed proteinuria that averaged 65 ± 7 mg/day (n = 10) at 9 mo, whereas proteinuria in normotensive salt-resistant SBN/y was 39 ± 4 mg/day (n = 10) (P < 0.01). Histopathological evaluation revealed focal and segmental glomerulosclerosis (FSGS) lesions grade 2 in SBH/y and normal histology in SBN/y. To amplify the differences between the strains, uninephrectomy was performed. At 9 mo, proteinuria in SBH/y with one kidney (SBH/y-1K) was 195 ± 12 mg/day (n = 10) and in SBN/y was 128 ± 10 mg/day (n = 10) (P < 0.001); histopathology revealed FSGS grade 3 in SBH/y-1K and grade 1–2 in SBN/y-1K. To determine the effect of salt loading, animals were provided with 8% NaCl in chow, causing hypertension in SBH/y but not in SBN/y. Proteinuria markedly increased in both SBH/y with two kidneys (SBH/y-2K) and SBH/y-1K, but not in SBN/y; histopathology revealed FSGS grade 1–2 in SBH/y-2K, grade 2 in SBH/y-1K, no lesions in SBN/y-2K, and grade 0–1 in SBN/y-1K. We concluded that the SBH/y strain is more susceptible to develop proteinuria and glomerulosclerosis than SBN/y. In search for the genetic basis of this phenomenon, we investigated the role of candidate proteinuric gene loci. Consomic strains were constructed by introgressing chromosome 1 (which harbors the rf-1 and rf-2 proteinuric loci) or chromosome 17 (which harbors rf-5) from SBH/y onto the SBN/y genomic background. The resulting consomic strains developed marked proteinuria that was severalfold higher than in SBN/y-1K; histopathological evaluation, however, revealed FSGS lesions grade 1–2, similar to those found in SBN/y-1K and less severe than in SBH/y-1K. These results suggest a functional role of gene systems located on chromosomes 1 and 17 in inducing proteinuria in the salt-susceptible Sabra rat strain. These genetic loci do not appear to harbor major genes for glomerulosclerosis.
salt sensitivity; SBH/y; SBN/y; consomic strains; quantitative trait loci
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