Modulation of blood pressure regulatory genes in the Agtrap ‐Plod1 locus associated with a deletion in Clcn6

In this study, we tested whether loss ofClcn6 would be protective against high salt-induced mortality. While we observed no significant differences in longevity or neuronal cell death between the SS-Clcn6 knock-out and SS-WT groups, we found that a mutation inClcn6 could be associated with changes to mRNA expression of nearbyMthfr,Nppa, andNppb genes, thereby complicating the genetic phenotype of our knockout animal. AbstractThe AGTRAP-PLOD1 locus is a conserved gene cluster containing several blood pressure regulatory genes, includingCLCN6,MTHFR,NPPA, andNPPB. Previous work revealed that knockout ofClcn6 on the Dahl Salt-Sensitive (SS) rat background (SS-Clcn6) resulted in lower diastolic blood pressure compared to SS-WT rats. Additionally, a recent study found sickle cell anemia patients with mutations inCLCN6 had improved survival and reduced stroke risk. We investigated whether loss ofClcn6 would delay the mortality of Dahl SS rats on an 8% NaCl (HS) diet. No significant difference in survival was found. The ability ofClcn6 to affect mRNA expression of nearbyMthfr, Nppa, andNppb genes was also tested. On normal salt (0.4% NaCl, NS) diets, renalMthfr mRNA and protein expression were significantly increased in the SS-Clcn6 rats. MTHFR reduces homocysteine to methionine, but no differences in circulating homocysteine levels were detected.Nppa mRNA levels in cardiac tissue from SS-Clcn6 rat in both normotensive and hypertensive conditions were significantly reduced compared t...
Source: Physiological Reports - Category: Physiology Authors: Tags: ORIGINAL ARTICLE Source Type: research