An earlier linkage analysis conducted on a population derived from the Dahl salt-sensitive hypertensive (S) and the spontaneously hypertensive rat (SHR) identified 10 genomic regions linked to several renal and/or cardiovascular traits. In particular, loci on rat chromosomes (RNO) 8 and 13 were linked to proteinuria, albuminuria, and renal damage. At both loci, the S allele was associated with increased proteinuria and renal damage. The current study aimed to confirm the linkage analysis and to evaluate the effect of genetic background on the ability of each locus (either RNO8 or RNO13) to exert a phenotypic difference when placed on a genetic background either susceptible (S rat) or resistant (SHR) to the development of renal disease. Congenic strains developed to transfer genomic segments from either RNO8 or RNO13 from the SHR onto the S genetic background [S.SHR(8) or S.SHR(13)] demonstrated significantly reduced proteinuria and improved renal function. Both congenic strains demonstrated significantly reduced glomerular and tubular injury, with renal interstitial fibrosis as the predominant pathological difference compared with the S. In contrast, transfer of RNO8 or RNO13 genomic regions from the S onto the resistant SHR genetic background [SHR.S(8) or SHR.S(13)] yielded no significant difference in proteinuria or glomerular, tubular, or interstitial injury compared with SHR. These findings demonstrate that genetic context plays a significant and important role in the phenotypic expression of genes influencing proteinuria on RNO8 and RNO13.