Abstract
The goal of the present study was to narrow a 1.37 Mbp region containing five genes on chromosome 13 (positions 80.92-82.29 Mbp in the Rn5 genome assembly) that we have previously found to influence the mean arterial pressure (MAP) by at least 25 mmHg in SS rats fed a high salt diet (8.0% NaCl for 14 days). The creation of 6 overlapping subcongenic strains that cover this region identified a 0.71 Mbp region (positions 81.01-81.72 Mbp) in which substitution of SS alleles with BN alleles reduced salt-induced hypertension in congenic SS rats by nearly 30 mmHg and significantly reduced urinary albumin excretion (UalbV) (see figure below; n=10-15/strain; * significant difference from SS; p<0.05). Analysis of the narrow candidate region revealed the presence of two protein-coding genes ( Pappa2 and Astn1 ) and a microRNA ( miR488 ), none of which are known to be mechanistically involved in hypertension. Pappa2 mRNA in these rat strains fed 0.4% NaCl diet was expressed at 6-10 fold higher levels in the renal cortex of the salt-resistant congenic strains with the BN allele (26-N, -O, and [[Unable to Display Character: &#8211;]]P) compared to strains with the SS allele (26-Q, -R, and [[Unable to Display Character: &#8211;]]S). A Pappa2 coding sequence variant of unknown functional importance was identified. Immunohistochemistry and fluorescence in situ hybridization studies localized Pappa2 to intercalated cells of the cortical and medullary collecting duct. Astn1 and miR-488 were not differentially expressed in renal tissue. Together, these findings point towards Pappa2 as a candidate gene for salt-induced hypertension in SS rats.
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