Abstract
Hypertension and proteinuria are important risk factors for cardiovascular morbidity and mortality. The Munich Wistar Frömter (MWF) rat represents an animal model for the identification of genetic factors, leading to spontaneous hypertension and proteinuria.
Male MWF rats demonstrated significantly elevated systolic blood pressure (SBP) values of 166.0+/-4.3 mmHg and an urinary albumin excretion (UAE) of 49.86+/-24.77 mg/24h as compared to normal Lewis rats. Female MWF animals showed somewhat lower systolic blood pressure values and normal albumin excretion rates compared to age matched male MWF rats. Moreover, MWF rats exhibit a significant number of surface glomeruli with and without direct renal surface contact in the cortex corticis region of the kidney.
MWF rats are resistant to salt loading when fed a diet containing 4% NaCl. In contrast, after high NaCl treatment (8% NaCl) SBP was significantly higher in both male and female MWF compared to MWF under normal diet. UAE was also significantly higher in male and female MWF animals after high NaCl excess compared to normal diet.
The results of the cosegregation and linkage analyses revealed that hypertension, increased urinary albumin excretion, and the presence of surface glomeruli are influenced by independent genetic loci, determined by a set of recessive genes.
Total genome scan analysis identified four Quantitative Trait Loci (QTL) on rat chromosomes 1, 6, 12, and 17, respectively, linked to urinary albumin excretion. Further analysis showed that homozygosity at least at three QTL was necessary to achieve an elevation of mean urinary albumin excretion levels above 10 mg/24h in adult backcross animals.
Moreover, linkage analysis indicated three independent blood pressure QTL on rat chromosome 1, 4, and 5, respectively. Independent loci influence the presence of superficial glomeruli without surface contact on the X-chromosome and with surface contact on chromosome 1 and 13.
We performed comparative gene expression analysis by a PCR-based cDNA subtraction method and by microarray-technique and identified differentially expressed mRNAs in the kidneys of MWF rats and the normotensive salt-resistant Lewis reference strain. Several candidate genes could be detected and are currently investigated.
The identification of genetic mechanisms leading to albuminuria and proteinuria in hypertension in the MWF model may provide new insights into the pathogenesis of similar conditions in human disease. |
