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1 Department of Clinical Pharmacology and Toxicology, University Medicine Charite, Campus Benjamin Franklin, Berlin, Germany
* To whom correspondence should be addressed. E-mail: kreutz{at}medizin.fu-berlin.de.
Our aim was to study the effects of high-salt diet on the genetics of albuminuria and renal injury in the Dahl salt-sensitive (SS) rat. We compared SS with salt-resistant spontaneously hypertensive rats (SHR) and with genetically related salt-sensitive stroke-prone SHR (SHRSP). Moreover, we performed genome-wide linkage analysis to identify quantitative trait loci (QTL) contributing to salt-induced renal injury in an F2-population derived from SS and SHR (n=230). In response to high-salt diet SS and SHRSP developed a striking increase in systolic blood pressure, urinary albumin excretion (UAE), and renal damage indices compared to SHR. Both SHRSP and SS developed severe glomerulosclerosis, while microangiopathy, tubulointerstitial fibrosis and inflammation were more pronounced in SHRSP. We detected two QTL with significant linkage to UAE on rat chromosomes (RNO) 6 and 19. Comparison with the recently identified salt-independent UAE QTL in young animals revealed that the UAE QTL on RNO6 is unique to high-salt conditions, while RNO19 plays a significant role during both low- and high-salt conditions. Some F2-animals demonstrated severe microangiopathy and tubulointerstitial injury, that exceeded the degree observed in the parental SS strain. Three loci demonstrated suggestive linkage to these phenotypes on RNO3, RNO5, and RNO20, while no linkage to glomerular damage was found. Further analyses at these loci indicated, that the severity of renal injury was attributable to the SHR-allele. Our data suggest, that the SHR genetic background confers greater susceptibility for the development of microangiopathy and tubulointerstitial injury in salt-sensitive hypertension than the SS background.
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