Rap1 ameliorates renal tubular injury in diabetic nephropathy.

Abstract

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.

• Authors: Li Xiao, Xuejing Zhu, Shikun Yang, Fuyou Liu, Zhiguang Zhou, Ming Zhan, Ping Xie, Dongshan Zhang, Jun Li, Panai Song, Yashpal S Kanwar, Lin Sun
• Journal: Diabetes (Diabetes) Vol. 63 Issue 4 Pg. 1366-80 (Apr 2014) ISSN: 1939-327X [Electronic] United States
• PMID: 24353183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• CCAAT-Enhancer-Binding Protein-beta
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• Transcription Factors
• RAP1B protein, human
• Rap1b protein, rat
• rap GTP-Binding Proteins

Topics

• Animals
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• CCAAT-Enhancer-Binding Protein-beta (antagonists & inhibitors)
• Cell Line
• Diabetes Mellitus, Experimental (metabolism)
• Diabetic Nephropathies (metabolism, physiopathology)
• Humans
• Kidney (drug effects, pathology)
• Kidney Tubules (drug effects, metabolism)
• Male
• Mitochondria (drug effects)
• Oxidative Stress (drug effects)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Transcription Factors (antagonists & inhibitors)
• rap GTP-Binding Proteins (metabolism)