Diabetes and hypertension in rodent models

As shown by ourselves and others, animals models closely resembling human complex diseases like IDDM in BB/OK and hypertension in SHR/Mol rats can be used to dissect a complex disease into discrete genetic factors as has been done for hypertension in (BB/OK x SHR/Mol) cross hybrids. Discrete genetic factors, so-called QTLs, were detected on chromosomes 1, 10, 18, 20, and X. To gain additional information about the physiologic effect of the mapped blood pressure QTLs, genetically defined regions of the SHR rat were transferred onto the genetic background of diabetes-prone BB/OK rats. Four new congenic BB.SHR rats named BB.Sa, BB.Bp2, BB.1K, and BB.Xs were generated and characterized telemetrically for blood pressure, heart rate, and motor activity. The data demonstrate clearly that each single blood pressure QTL of the SHR rat causes a significant increase of the systolic blood pressure and has a different influence on diastolic blood pressure, heart rate, and motor activity. The effects were modified differently by the diabetic state in BB.Sa, BB.Bp2, and BB.Xs rats carrying all diabetogenic genes of the BB/OK rats. The results demonstrate that these newly established congenic strains are a unique tool to study the physiological control of blood pressure by a single blood pressure QTL on the one hand and their interaction with hyperglycemia on the other. It is well within the bounds of possibility that diabetic congenics reflect the diabetic hypertension seen in diabetic patients. Because of the synteny conservation in gene order between different mammals, genes of the appropriate human region could therefore be candidate genes for hypertension in diabetics. Furthermore, these congenic strains can also be used to study interactions between a blood pressure QTL and various selected environmental conditions. In this way, one could learn which QTL can be influenced by environmental factors and to what extent. Another point is the study of gene interactions. Because congenics are genetically identical except for the defined transferred region, congenics can be crossed to investigate the interaction between two or three blood pressure QTLs selected by the investigator and not by nature. These QTL combinations can be studied in the nondiabetic as well as diabetic state. Although the advantage of congenic strains has been shown, the transferred chromosomal regions are too large to pinpoint the gene responsible for the phenotypic change. Therefore, regions on each chromosome must be systematically whittled down, which can be done by crossing the congenics with BB/OK rats and intercrossing their progeny to generate recombinants. These can then be used for the creation of new congenic lines carrying a much smaller region of the SHR/Mol rat. This has been started for the region on chromosome 1 spanning a 16-cM region from the Sa to the Igf2 gene. BB.Sa rats were therefore backcrossed onto BB/OK rats and the resulting progeny were intercrossed. The aim will be to create at least three new congenic BB.Sa rat strains homozygous for the SHR alleles of Sa, Lsn, or Igf2 genes. However, new problems will emerge with these new congenics. To genetically define small regions requires more dense polymorphic markers than are currently available. Dense polymorphic markers will also be necessary to split the other regions on chromosomes 10, 18, 20, and X. We expect that in the near future it will be possible using this approach to define small regions of < 0.5 cM. The recent progress in gene mapping in the rat gives hope that the use of such congenic lines will allow the identification and recovery of the blood pressure genes in the near future.