Abstract 319: Overexpression of microRNA-429 into the Renal Medulla Attenuated Salt-sensitive Hypertension in Dahl S Rats
HIF prolyl-hydroxylase 2 (PHD2) is an enzyme to promote the degradation of transcription factor hypoxia inducible factor (HIF)-1α. We have previously shown that high salt intake stimulates the expression of microRNA (miR)-429, which promotes the decay of HIF prolyl-hydroxylase 2 (PHD2) mRNA, and that reduction of PHD2 mRNA level leads to the accumulation of HIF-1α and activation of many HIF-1α-regulated antihypertensive genes such as nitric oxide synthase (NOS) 2 and heme oxygenase 1 in the renal medulla. This miR-429-mediated regulation of PHD2/HIF-1α pathway is an important molecular adaptation to promote extra sodium excretion and maintain blood pressure. However the high salt-induced increase in the renal medullary miR-429 level was impaired in Dahl S rat, a salt-sensitive hypertension model. The present study determined whether overexpression of miR-429 would reduce the levels of PHD2 mRNA, increase the expression of HIF-1α target genes in the renal medulla, and consequently attenuate salt-sensitive hypertension in Dahl S rats. Renal medullary miR-429 levels were increased by 2-fold via transfection of miR-429-expressing plasmid into the renal medulla in Dahl S rats, which was accompanied by 40% (0.4 of 1) decrease in PHD2 mRNA levels and 2-fold increase in NOS2 mRNA expression compared with scramble-miR-treated rats. Functionally, chronic high salt-induced sodium retention was remarkably reduced from 28.6 ± 2.4 mmole/kg in control rats to 18.5 ± 1.6 mmole/kg in miR-429-treated rats. Furthermore, hypertension induced by 2-week high salt intake was significantly attenuated in miR-429-treated rats. The mean arterial pressure in these Dahl S rats was 111.8 ± 1.7 mmHg on a low salt diet, 143.7 ± 4.1 on a high salt diet, and 128.6 ± 2.2 on a high salt diet treated with miR-429 plasmids, respectively. These results suggest that the impaired miR-429-mediated PHD2 inhibition in response to high salt intake in the renal medulla may represent a novel mechanism for hypertension in Dahl S rats and that correction of this impairment in miR-429 could be a therapeutic approach for salt-sensitive hypertension.
Author Disclosures: Q. Zhu: None. J. Hu: None. Z. Wang: None. P. Li: None. N. Li: None.
- © 2014 by American Heart Association, Inc.