Rap1 ameliorates renal tubular injury in diabetic nephropathy
- Li Xiao1,
- Xuejing Zhu1,*,
- Shikun Yang1,
- Fuyou Liu1,
- Zhiguang Zhou2,
- Ming Zhan3,
- Ping Xie3,
- Dongshan Zhang1,
- Jun Li1,
- Panai Song1,
- Yashpal S Kanwar3 and
- Lin Sun1⇑
- 1Department of Nephrology
- 2Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- 3Departments of Pathology & Medicine, Northwestern University, Chicago, Illinois, USA
- Correspondence address: Lin Sun, E-mail:
Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remains unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress.The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN was examined in rats with Streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Over-expression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-β and PGC-1α. Furthermore, Rap1b G12V also decreased phosphorylation of Drp1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced treated with HG. These effects were imitated by transfection with C/EBP-β or PGC-1α siRNA. In addition, Rap1b could modulate C/EBP-β binding to the endogenous PGC-1α promoter and the interaction between PGC-1α and Catalase or mitochondrial superoxide dismutase. Indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-β:PGC-1α signaling.
* Li Xiao and Xuejing Zhu contributed equally to this work.
- Received September 15, 2013.
- Accepted December 3, 2013.
- © 2013 by the American Diabetes Association.
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