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

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 and Mingyu Liang
JASN July 2020, 31 (7) 1539-1554; DOI: https://doi.org/10.1681/ASN.2019101100
Yuan Cheng
1Department of Nephrology, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Clinical Institute of Anhui Medical University, Shenzhen, People’s Republic of China
2The Center for Nephrology and Urology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, People’s Republic of China
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Dandan Wang
2The Center for Nephrology and Urology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, People’s Republic of China
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
4Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
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Feng Wang
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
5Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China
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Jing Liu
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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  • ORCID record for Jing Liu
Baorui Huang
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
5Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China
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Maria Angeles Baker
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Jianyong Yin
5Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China
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Rui Wu
5Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China
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Xuanchen Liu
5Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China
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Kevin R. Regner
6Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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Kristie Usa
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Yong Liu
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Congxiao Zhang
7Section of Epithelial and Retinal Physiology and Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland
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Lijin Dong
7Section of Epithelial and Retinal Physiology and Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland
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Aron M. Geurts
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Niansong Wang
5Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China
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Sheldon S. Miller
7Section of Epithelial and Retinal Physiology and Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland
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Yongcheng He
8Department of Nephrology, Shenzhen Hengsheng Hospital, Shenzhen, Guangdong, People’s Republic of China
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Mingyu Liang
3Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Significance Statement

Several microRNAs have been shown to play significant roles in the development of renal injury. The microRNA miR-204-5p is highly enriched in the kidney but its involvement in chronic renal injury is unknown. In this study, the authors report that miR-204-5p abundance is significantly decreased in kidney biopsy samples from patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy. They also found, in a rat model of salt-sensitive hypertension, a mouse model of hypertension, and a mouse model of type 2 diabetes, inhibition of miR-204-5p, or deletion of the Mir204 gene results in upregulation of an injurious molecular pathway and substantial exacerbation of renal injury. These findings provide evidence of a prominent role for miR-204-5p in safeguarding the kidneys against common causes of chronic renal injury.

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.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.

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.

  • chronic renal disease
  • albuminuria
  • microRNA
  • hypertension
  • diabetes
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (7)
Journal of the American Society of Nephrology
Vol. 31, Issue 7
July 2020
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Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes
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
JASN Jul 2020, 31 (7) 1539-1554; DOI: 10.1681/ASN.2019101100

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Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes
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
JASN Jul 2020, 31 (7) 1539-1554; DOI: 10.1681/ASN.2019101100
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  • hypertension
  • diabetes

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