Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes.

Journal of the American Society of Nephrology : JASN 2020 Jul

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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. 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. 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.13BN26 rats. Administering anti-miR-204-5p to SS.13BN26 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. 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. Copyright © 2020 by the American Society of Nephrology.

Citation

Yuan Cheng, Dandan Wang, Feng Wang, Jing Liu, Baorui Huang, Maria Angeles Baker, Jianyong Yin, Rui Wu, Xuanchen Liu, Kevin R Regner, Kristie Usa, Yong Liu, Congxiao Zhang, Lijin Dong, Aron M Geurts, Niansong Wang, Sheldon S Miller, Yongcheng He, Mingyu Liang. Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes. Journal of the American Society of Nephrology : JASN. 2020 Jul;31(7):1539-1554