Faculty Collaboration Database

Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes. J Am Soc Nephrol 2020 Jul;31(7):1539-1554

Date

06/04/2020

Pubmed ID

32487559

Pubmed Central ID

PMC7350998

DOI

10.1681/ASN.2019101100

Scopus ID

2-s2.0-85087468924 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

BACKGROUND: Aberrant microRNA (miRNA) expression affects biologic processes and downstream genes that are crucial to CKD initiation or progression. The miRNA miR-204-5p is highly expressed in the kidney but whether miR-204-5p plays any role in the development of chronic renal injury is unknown.

METHODS: We used real-time PCR to determine levels of miR-204 in human kidney biopsies and animal models. We generated Mir204 knockout mice and used locked nucleic acid-modified anti-miR to knock down miR-204-5p in mice and rats. We used a number of physiologic, histologic, and molecular techniques to analyze the potential role of miR-204-5p in three models of renal injury.

RESULTS: Kidneys of patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy exhibited a significant decrease in miR-204-5p compared with controls. Dahl salt-sensitive rats displayed lower levels of renal miR-204-5p compared with partially protected congenic SS.13^BN26 rats. Administering anti-miR-204-5p to SS.13^BN26 rats exacerbated interlobular artery thickening and renal interstitial fibrosis. In a mouse model of hypertensive renal injury induced by uninephrectomy, angiotensin II, and a high-salt diet, Mir204 gene knockout significantly exacerbated albuminuria, renal interstitial fibrosis, and interlobular artery thickening, despite attenuation of hypertension. In diabetic db/db mice, administering anti-miR-204-5p exacerbated albuminuria and cortical fibrosis without influencing blood glucose levels. In all three models, inhibiting miR-204-5p or deleting Mir204 led to upregulation of protein tyrosine phosphatase SHP2, a target gene of miR-204-5p, and increased phosphorylation of signal transducer and activator of transcription 3, or STAT3, which is an injury-promoting effector of SHP2.

CONCLUSIONS: These findings indicate that the highly expressed miR-204-5p plays a prominent role in safeguarding the kidneys against common causes of chronic renal injury.

Author List

Cheng Y, Wang D, Wang F, Liu J, Huang B, Baker MA, Yin J, Wu R, Liu X, Regner KR, Usa K, Liu Y, Zhang C, Dong L, Geurts AM, Wang N, Miller SS, He Y, Liang M

Authors

Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Kevin 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

Adult
Albuminuria
Animals
Arteries
Blood Pressure
Diabetic Nephropathies
Female
Fibrosis
Gene Knockdown Techniques
Humans
Hypertension
Kidney
Male
Mice
Mice, Knockout
MicroRNAs
Middle Aged
Nephrosclerosis
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Rats
Real-Time Polymerase Chain Reaction
STAT3 Transcription Factor
Signal Transduction
Sodium Chloride, Dietary
Up-Regulation