Contribution of Genetic Factors to Renal Lesions in the Stroke-Prone Spontaneously Hypertensive Rat

Stroke-prone spontaneously hypertensive rats (SHRSP) develop renal lesions more frequently than the closely related control strain, the stroke-resistant SHR. The aim of this study was to investigate the contribution of genetic factors to the enhanced susceptibility to renal damage of SHRSP in an SHRSP/SHR F2 intercross by means of a genotype/phenotype cosegregation analysis. For this purpose, 154 6-week-old F2-SHRSP/SHR rats (79 male, 75 female) were fed a stroke-permissive Japanese diet for 4 weeks. Systolic blood pressure (SBP) was recorded at the end of the dietary period. Renal damage was scored from 0 to 3, and 274 genetic markers polymorphic between SHR and SHRSP were genotyped. Linkage of genotype markers to the degree of renal disease was determined by chi2 test. Experimental threshold level to declare linkage was calculated by QTL cartographer. SBP was not correlated to renal damage (rho coefficient, 0.201; P=NS). Grade 2 and grade 3 lesions were more frequent in male than in female rats (P=0.01). Two loci, D1Rat238, on chromosome 1 and the IGF receptor-binding protein 4 (Rbp4g) on chromosome 10, were significantly linked to the degree of renal damage, with SHRSP allele being aggressive at D1Rat238 locus and protective at Rbp4g locus. In male rats only, the SHRSP allele at one locus on chromosome 16, D16Mit2, was associated with a more severe degree of renal disease. Our results demonstrate that in this intercross, susceptibility to renal damage is influenced by several genetic loci acting independently from high blood pressure levels and also shows a sexual dimorphism.