title: Klotho gene delivery ameliorates renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats by suppressing the Rho-associated coiled-coil kinase signaling pathway.
abstract: The present study aimed to investigate whether klotho gene delivery attenuated renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats. A recombinant adeno-associated virus (rAAV) carrying mouse klotho full-length cDNA (rAAV.mKL), was constructed for in vivo investigation of klotho expression. Diabetes was induced in rats by a single tail vein injection of 60 mg/kg streptozotocin. Subsequently, the diabetic rats received an intravenous injection of rAAV.mKL, rAAV.green fluorescent protein (GFP) or phosphate-buffered saline (PBS). The Sprague-Dawley rat group received PBS and served as the control group. After 12 weeks, all the rats were sacrificed and ELISA, immunohistochemical and histological analyses, fluorescence microscopy, semi-quantitative reverse transcription-polymerase chain reaction and western blottin were performed. A single dose of rAAV.mKL was found to prevent the progression of renal hypertrophy and fibrosis for at least 12 weeks (duration of study). Klotho expression was suppressed in the diabetic rats, but was increased by rAAV.mKL delivery. rAAV.mKL significantly suppressed diabetes-induced renal hypertrophy and histopathological changes, reduced renal collagen fiber generation and decreased kidney hypertrophy index. In addition, rAAV.mKL decreased the protein expression levels of fibronectin and vimentin, while it downregulated the mRNA expression and activity of Rho-associated coiled-coil kinase (ROCK)I in the kidneys of the diabetic rats. These results indicated that klotho gene delivery ameliorated renal hypertrophy and fibrosis in diabetic rats, possibly by suppressing the ROCK signaling pathway. This may offer a novel approach for the long-term control and renoprotection of diabetes.
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Minghong
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Yunkui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Qiuchen
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Houxun
authors.initials: H
authors.lastname: Ma
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000628:therapy; D003930:Diabetic Retinopathy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005355:Fibrosis / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005966:Glucuronidase / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D006984:Hypertrophy / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D000090265:Klotho Proteins; D051379:Mice; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C578418:ROCK1 protein, rat; D054460:rho-Associated Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins