Overexpression of MicroRNA-429 Transgene Into the Renal Medulla Attenuated Salt-Sensitive Hypertension in Dahl S Rats. (5th June 2021)

• Record Type: Journal Article
• Authors: Zhu, Qing; Hu, Junping; Wang, Lei; Wang, Weili; Wang, Zhengchao; Li, Pin-Lan; Li, Ningjun
• Is Part Of: American journal of hypertension. Volume 34:Number 10(2021)
• Page Start: 1071
• Page End: 1077
• Publication Date: 2021-06-05
• Subjects: blood pressure -- hypertension -- hypoxia-inducible factor -- microRNA -- nitric oxide synthase 2 -- sodium excretion; Hypertension -- Periodicals; 616.132005
• DOI: 10.1093/ajh/hpab089
• Languages: English
• ISSNs: 0895-7061

Abstract

Abstract: Background: We have previously shown that high salt stimulates the expression of miR-429 in the renal medulla, which induces mRNA decay of HIF prolyl-hydroxylase 2 (PHD2), an enzyme to promote the degradation of hypoxia-inducible factor (HIF)-1α, and increases the HIF-1α-mediated activation of antihypertensive genes in the renal medulla, consequently promoting extra sodium excretion. Our preliminary results showed that high salt-induced increase of miR-429 was not observed in Dahl S rats. This present study determined whether correction of this impairment in miR-429 would reduce PHD2 levels, increase antihypertensive gene expression in the renal medulla and attenuate salt-sensitive hypertension in Dahl S rats. Methods: Lentiviruses encoding rat miR-429 were transfected into the renal medulla in uninephrectomized Dahl S rats. Sodium excretion and blood pressure were then measured. Results: Transduction of lentiviruses expressing miR-429 into the renal medulla increased miR-429 levels, decreased PHD2 levels, and upregulated HIF-1α target gene NOS-2, which restored the adaptive mechanism to increase the antihypertensive gene after high-salt intake in Dahl S rats. Functionally, overexpression of miR-429 transgene in the renal medulla significantly improved pressure natriuretic response, enhanced urinary sodium excretion, and reduced sodium retention upon extra sodium loading, and consequently, attenuated the salt-sensitive hypertension in Dahl S rats. Conclusions: Our results suggest that the impaired miR-429-mediated PHD2 inhibition in response to high salt in the renal medulla may represent a novel mechanism for salt-sensitive hypertension in Dahl S rats and that correction of this impairment in miR-429 pathway could be a therapeutic approach for salt-sensitive hypertension. Graphical Abstract: