title: 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.affiliation: Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Xuejing
authors.initials: X
authors.lastname: Zhu
authors.forename: Shikun
authors.initials: S
authors.lastname: Yang
authors.forename: Fuyou
authors.initials: F
authors.lastname: Liu
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Dongshan
authors.initials: D
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Panai
authors.initials: P
authors.lastname: Song
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D022782:CCAAT-Enhancer-Binding Protein-beta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; C116753:RAP1B protein, human; C492135:Rap1b protein, rat; D020668:rap GTP-Binding Proteins