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Articles in PresS, published online ahead of print April 23, 2002
Physiol Genomics, 10.1152/physiolgenomics.00014.2002
Submitted on February 8, 2002
Accepted on April 18, 2002
1 Laboratory for Molecular Medicine and Rat Genome Center, Barzilai Medical Center Campus of the Ben-Gurion University, Ashkelon, Israel
2 Pathology Department, Shaare Zedeq Medical Center, Jerusalem, Israel
* To whom correspondence should be addressed. E-mail: labmomed{at}bgumail.bgu.ac.il.
In search for 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 months, while 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 months, proteinuria in SBH/y-1K (with 1 kidney) was 195 ± 12 mg/day (n=10) and in SBN/y 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 2K (2 kidneys) and 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 several fold 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.
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