Overexpression of MicroRNA-429 Transgene Into the Renal Medulla Attenuated Salt-Sensitive Hypertension in Dahl S Rats.

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.

• Authors: Qing Zhu, Junping Hu, Lei Wang, Weili Wang, Zhengchao Wang, Pin-Lan Li, Ningjun Li
• Journal: American journal of hypertension (Am J Hypertens) Vol. 34 Issue 10 Pg. 1071-1077 (10 27 2021) ISSN: 1941-7225 [Electronic] United States
• PMID: 34089591 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• MicroRNAs
• Sodium Chloride, Dietary

Topics

• Animals
• Gene Expression
• Hypertension (chemically induced, genetics)
• Kidney Medulla (metabolism, physiopathology)
• MicroRNAs (genetics)
• Rats
• Rats, Inbred Dahl
• Sodium Chloride, Dietary (pharmacology)
• Transgenes