Yuan Cheng1,2,3, Dandan Wang2,3,4, Feng Wang3,5, Jing Liu3, Baorui Huang3,5, Maria Angeles Baker3, Jianyong Yin5, Rui Wu5, Xuanchen Liu5, Kevin R Regner6, Kristie Usa3, Yong Liu3, Congxiao Zhang7, Lijin Dong7, Aron M Geurts3, Niansong Wang5, Sheldon S Miller7, Yongcheng He8, Mingyu Liang9. 1. Department 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. 2. The Center for Nephrology and Urology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, People's Republic of China. 3. Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin. 4. Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People's Republic of China. 5. Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China. 6. Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. 7. Section of Epithelial and Retinal Physiology and Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland. 8. Department of Nephrology, Shenzhen Hengsheng Hospital, Shenzhen, Guangdong, People's Republic of China mliang@mcw.edu heyongcheng@medmail.com.cn. 9. Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin mliang@mcw.edu heyongcheng@medmail.com.cn.
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.
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.
Authors: Jian-dong Zhang; Mehul B Patel; Young-Soo Song; Robert Griffiths; James Burchette; Phillip Ruiz; Matthew A Sparks; Ming Yan; David N Howell; Jose A Gomez; Robert F Spurney; Thomas M Coffman; Steven D Crowley Journal: Circ Res Date: 2012-04-24 Impact factor: 17.367
Authors: Limin Lu; Peigang Li; Chun Yang; Terry Kurth; Michael Misale; Meredith Skelton; Carol Moreno; Richard J Roman; Andrew S Greene; Howard J Jacob; Jozef Lazar; Mingyu Liang; Allen W Cowley Journal: Physiol Genomics Date: 2009-12-15 Impact factor: 3.107
Authors: Fatiha Tabet; Ernesto L Schiffrin; Glaucia E Callera; Ying He; Guoying Yao; Arne Ostman; Kai Kappert; Nicholas K Tonks; Rhian M Touyz Journal: Circ Res Date: 2008-06-19 Impact factor: 17.367