Genetic Dissection of Hypertension Related Renal Disease Using the Dahl Salt-Sensitive Rat
Chronic kidney disease (CKD) is an important medical problem worldwide that can, left undiagnosed and untreated, develop into end stage renal failure. Unfortunately, knowledge of the genetic factors that cause CKD is limited, except for some monogenic forms of kidney disease. It is our goal to understand the genetic basis of renal disease observed in the Dahl salt-sensitive (S) rat, a model of hypertension and renal disease and ultimately apply this knowledge to humans. An initial linkage analysis for urinary protein excretion (UPE), including several other renal and cardiovascular traits was performed at multiple time points using a backcross population derived from the S rat and the spontaneously hypertensive rat (SHR). The study identified 10 quantitative trait loci (QTL) linked to renal damage and/or function independent from the effects of saltloading. A second linkage analysis sought to examine the effect of salt-loading on the observation of UPE QTL using a backcross population raised on 2% NaCl. The second linkage analysis confirmed the results of the first and identified that UPE QTL on chromosome 2, 11, and 19 were influenced by salt-loading. Congenic strains were developed on select chromosomes (2, 6, 9, 11, and 13) to confirm the linkage analysis and to examine the effect of each QTL individually on the S background. These congenic strains demonstrated large and significant effects on UPE compared to the S rat. Further work sought to characterize the chromosome 2 congenic [S.SHR(2)] strain by conducting a time-course analysis (wk 4 to 20), including evaluating several renal parameters, histology, electron microscopy, and gene expression/pathway analysis. Throughout the time course the congenic strain consistently maintained a two-fold reduction in UPE, and significantly reduced glomerular, tubular and interstitial changes. Gene expression/pathway analysis revealed that pathways involved in cellular assembly and organization, cellular movement, and immune response were controlled differently between the S and congenic providing a potential mechanism of the QTL. Fine-mapping using recombinant progeny testing (RPT) further reduced the QTL region to contain 64 known and/or predicted gene, including several interesting candidate genes.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:renal disease linkage analysis positional cloning congenic strain dahl s rat hypertension
Date of Publication:01/01/2006