Physiological Genomics of the Rat Renal Failure QTLs Rf-1 through Rf-5

Linkage analysis of a cross of FHH and renal-resistant ACI rats revealed five QTLs, named Rf-1 through Rf-5 influencing susceptibility to renal damage. This thesis describes the physiological genomics of the rat renal failure QTLs Rf-1 through Rf-5. Congenic rats were generated carrying one of the Rf-QTLs or the Rf-1 in combination with another Rf-QTL. Experiments were performed on Rf-1, Rf-3, Rf-4 and Rf-5 single congenics, and Rf-1+2, Rf-1+3, Rf-1+4, Rf-1+4 and Rf-1+5 double congenic rats. Susceptibility to the development of renal damage was assessed using four models, i.e. the two-kidney (2K) control situation, 2K with L-NAME induced hypertension, unilateral nephrectomy (UNX), and UNX with LNAME induced hypertension. Since previous studies showed that FHH rats have an impaired renal blood flow autoregulation, all congenic rats were tested for the presence of renal blood flow autoregulation. Besides these experiments we also tested the applicability of the remnant kidney model (RKM) to assess differences between the Rf-congenic strains. The outcome of the various physiological genomic studies presented in this thesis regarding the rat renal failure QTLs Rf-1 through Rf-5 led to the following conclusions: The Rf-1 region of the FHH contains one or more genes directly influencing renal susceptibility and impairing renal autoregulation. Whether these genes are the same needs to be further investigated. The direct effect of the Rf-2 region could not yet be tested. When the Rf-2 region is combined with the Rf-1 region, a significant increase in renal damage is seen when compared with Rf-1 alone. Furthermore, the Rf2 region, also harboring the blood pressure QTL Bpfh-1, increases blood pressure. The Rf-3 region contains genes directly influencing renal susceptibility. Renal damage susceptibility in Rf-3 single congenics is comparable to that of Rf-1 single congenics. When Rf-1 and Rf-3 are combined a significant synergistic interaction is present. The Rf-3 congenic rats do have a normal renal autoregulation. The mechanisms by which Rf-3 influences the development of renal damage still remains to be detected. Genes in the Rf-4 region do not directly influence renal susceptibility. However, when combined with Rf-1 a significant synergistic interaction is present. The Rf-4 congenic rats do have a normal autoregulation. The mechanisms by which Rf-4 indirectly influences the development of renal damage is still unknown and should be further investigated. The Rf-5 region does not contain genes that directly influence renal susceptibility. In addition, the Rf-5 region shows no synergistic interaction with the Rf-1 region. The RKM is not a very suitable model to analyze renal susceptibility in rats carrying Rf-regions of the FHH rats. The four models we used, especially the UNX and 2K+L-NAME model appear more suitable to assess differences in susceptibility to develop renal damage.

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