title: Early protective effect of mitofusion 2 overexpression in STZ-induced diabetic rat kidney.
abstract: Diabetic nephropathy (DN) is a serious complication of diabetes with a poorly defined etiology and limited treatment options. Early intervention is key to preventing the progression of DN. Mitofusin 2 (Mfn2) regulates mitochondrial morphology and signaling, and is involved in the pathogenesis of numerous diseases. Furthermore, Mfn2 is also closely associated with the development of diabetes, but its functional roles in the diabetic kidney remain unknown. This study investigated the effect of Mfn2 at an early stage of DN. Mfn2 was overexpressed by adenovirus-mediated gene transfer in streptozotocin-induced diabetic rats. Clinical parameters (proteinuria, albumin/creatinine ratio), pathological changes, ultra-microstructural changes in nephrons, expression of collagen IV and phosph-p38, ROS production, mitochondrial function, and apoptosis were evaluated and compared with diabetic rats expressing control levels of Mfn2. Endogenous Mfn2 expression decreased with time in DN. Compared to the blank transfection control group, overexpression of Mfn2 decreased kidney weight relative to body weight, reduced proteinuria and ACR, and improved pathological changes typical of the diabetic kidney, like enlargement of glomeruli, accumulation of ECM, and thickening of the basement membrane. In addition, Mfn2 overexpression inhibited activation of p38, and the accumulation of ROS; prevented mitochondrial dysfunction; and reduced the synthesis of collagen IV, but did not affect apoptosis of kidney cells. This study demonstrates that Mfn2 overexpression can attenuate pathological changes in the kidneys of diabetic rats. Further studies are needed to clarify the underlying mechanism of this protective function. Mfn2 might be a potential therapeutic target for the treatment of early stage DN.
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China. kidney123@163.com
authors.forename: Wan Xin
authors.initials: WX
authors.lastname: Tang
authors.forename: Wei Hua
authors.initials: WH
authors.lastname: Wu
authors.forename: Xiao Xi
authors.initials: XX
authors.lastname: Zeng
authors.forename: Hong
authors.initials: H
authors.lastname: Bo
authors.forename: Song Min
authors.initials: SM
authors.lastname: Huang
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases; D015316:Genetic Therapy; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use*; D009929:Organ Size; D018384:Oxidative Stress; D011507:Proteinuria / Q000517:prevention & control; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013311:Streptozocin; D000105:Acetyl Coenzyme A; D048051:p38 Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
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