Transfer of a Single Genomic Region (RF-1) from the Fawn-Hooded Hypertensive Rat Onto the Genomic Background of the Aci Rat Results in Renal Impairment

52 The fawn-hooded hypertensive (FHH) rat is an excellent experimental model to analyse the genetics of hypertension-associated renal damage. Male FHH rats spontaneously develop moderate hypertension and marked proteinuria early in life. Previous linkage analyses with crosses between FHH and ACI rats, revealed that at least five quantitative trait loci (QTLs), named Rf-1 to Rf-5 , were linked to proteinuria. The Rf-1 locus on rat chromosome 1 had by far the highest LOD-score suggesting a major role in determining the severity of renal failure. The next step to identify the importance of the various QTLs is the generation of congenic strains for all five chromosomal regions. Here we report the first results obtained in Rf-1 congenic rats. Using marker-assisted backcrossing, we transferred the Rf-1 region, between the markers D1Mit34 and D1Mit156, from the FHH genome onto the genomic background of the normotensive ACI rat. To determine the impact of Rf-1 o n the development of renal damage, we challenged the renal hemodynamic function of these congenic animals by unilateral nephrectomy (UNX) alone, or in combination with L-NAME-induced hypertension. The parental ACI strain was used as control. The various experimental groups consisted of 10-12 rats. During a 24 week follow-up period after UNX, the congenic strain, officially named ACI.FHH- D1Mit34/Mit156 ( Rf-1B for short), did develop significantly more proteinuria and albuminuria than the ACI rats. The differences between the Rf-1B congenic and ACI rats were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mm Hg, i.e. the level of hypertension normally present in the parental FHH strain. Histological analysis of the kidney showed that the incidence of glomerulosclerosis was also higher in the Rf-1B congenic rats. These findings provide the first direct evidence that the Rf-1 region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increased blood pressure.