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J Clin Med. 2018 Nov 22;7(12). pii: E468. doi: 10.3390/jcm7120468.

The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy.

Tsai YC1,2,3,4,5, Kuo PL6, Kuo MC7,8,9,10, Hung WW11, Wu LY12, Chang WA13,14, Wu PH15,16, Lee SC17, Chen HC18,19, Hsu YL20.

Author information

1
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. lidam65@yahoo.com.tw.
2
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. lidam65@yahoo.com.tw.
3
Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. lidam65@yahoo.com.tw.
4
Division of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. lidam65@yahoo.com.tw.
5
Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. lidam65@yahoo.com.tw.
6
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. kuopolin@seed.net.tw.
7
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. mechku@kmu.edu.tw.
8
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. mechku@kmu.edu.tw.
9
Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. mechku@kmu.edu.tw.
10
Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. mechku@kmu.edu.tw.
11
Division of Endocrinology and Metabolism, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. hung4488@ms57.hinet.net.
12
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. esther906@gmail.com.
13
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. 960215kmuh@gmail.com.
14
Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. 960215kmuh@gmail.com.
15
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. 970392@mail.kmuh.org.tw.
16
Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. 970392@mail.kmuh.org.tw.
17
Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. suchle5910@gmail.com.
18
Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. chenhc@kmu.edu.tw.
19
Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. chenhc@kmu.edu.tw.
20
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. hsuyl326@gmail.com.

Abstract

Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG-induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence-associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN.

KEYWORDS:

Skp2; cell senescence; diabetic nephropathy; miR-378i; proximal tubular epithelial cell

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