Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy
- Li Xiao1,
- Xuejing Zhu1,
- Shikun Yang1,
- Fuyou Liu1,
- Zhiguang Zhou2,
- Ming Zhan3,4,
- Ping Xie3,4,
- Dongshan Zhang1,
- Jun Li1,
- Panai Song1,
- Yashpal S. Kanwar3,4 and
- Lin Sun1⇑
- 1Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- 2Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- 3Department of Pathology, Northwestern University, Chicago, IL
- 4Department of Medicine, Northwestern University, Chicago, IL
- Corresponding author: Lin Sun, .
L.X. and X.Z. contributed equally to this work.
Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain 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 were 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. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and 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 Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-β or PGC-1α short interfering RNA. 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1412/-/DC1.
- Received September 15, 2013.
- Accepted December 4, 2013.
- © 2014 by the American Diabetes Association.
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