MicroRNA-214-3p in the Kidney Contributes to the Development of Hypertension. J Am Soc Nephrol 2018 Oct;29(10):2518-2528
Date
07/28/2018Pubmed ID
30049682Pubmed Central ID
PMC6171279DOI
10.1681/ASN.2018020117Scopus ID
2-s2.0-85053979457 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
BACKGROUND: In spite of extensive study, the mechanisms for salt sensitivity of BP in humans and rodent models remain poorly understood. Several microRNAs (miRNAs) have been associated with hypertension, but few have been shown to contribute to its development.
METHODS: We examined miRNA expression profiles in human kidney biopsy samples and rat models using small RNA deep sequencing. To inhibit an miRNA specifically in the kidney in conscious, freely moving rats, we placed indwelling catheters to allow both renal interstitial administration of a specific anti-miR and measurement of BP. A rat with heterozygous disruption of the gene encoding endothelial nitric oxide synthase (eNOS) was developed. We used bioinformatic analysis to evaluate the relationship between 283 BP-associated human single-nucleotide polymorphisms (SNPs) and 1870 human miRNA precursors, as well as other molecular and cellular methods.
RESULTS: Compared with salt-insensitive SS.13BN26 rats, Dahl salt-sensitive (SS) rats showed an upregulation of miR-214-3p, encoded by a gene in the SS.13BN26 congenic region. Kidney-specific inhibition of miR-214-3p significantly attenuated salt-induced hypertension and albuminuria in SS rats. miR-214-3p directly targeted eNOS. The effect of miR-214-3p inhibition on hypertension and albuminuria was abrogated in SS rats with heterozygous loss of eNOS. Human kidney biopsy specimens from patients with hypertension or hypertensive nephrosclerosis showed upregulation of miR-214-3p; the gene encoding miR-214-3p was one of several differentially expressed miRNA genes located in proximity to human BP-associated SNPs.
CONCLUSIONS: Renal miR-214-3p plays a functional and potentially genetic role in the development of hypertension, which might be mediated in part by targeting eNOS.
Author List
Liu Y, Usa K, Wang F, Liu P, Geurts AM, Li J, Williams AM, Regner KR, Kong Y, Liu H, Nie J, Liang MAuthors
Aron Geurts PhD Professor in the Physiology department at Medical College of WisconsinKevin R. Regner MD Interim Chair, Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAnimals
Blood Pressure
Disease Models, Animal
Female
Gene Knockout Techniques
Humans
Hypertension
Kidney
Male
MicroRNAs
Middle Aged
Nephrosclerosis
Nitric Oxide Synthase Type III
Polymorphism, Single Nucleotide
Rats
Rats, Inbred Dahl
Rats, Transgenic
Transcriptome
Up-Regulation
