Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Endocrine. 2012 Apr;41(2):236-47. doi: 10.1007/s12020-011-9555-1. Epub 2011 Nov 18.
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.
糖尿病肾病（DN）是糖尿病的一种严重并发症，其病因尚不清楚，治疗选择有限。早期干预是预防 DN 进展的关键。线粒体融合蛋白 2（Mfn2）调节线粒体形态和信号转导，参与多种疾病的发病机制。此外，Mfn2 也与糖尿病的发生密切相关，但它在糖尿病肾脏中的功能作用尚不清楚。本研究探讨了 Mfn2 在 DN 早期的作用。通过腺病毒介导的基因转染在链脲佐菌素诱导的糖尿病大鼠中过表达 Mfn2。评估并比较了糖尿病大鼠中 Mfn2 表达水平的变化与临床参数（蛋白尿、白蛋白/肌酐比）、病理变化、肾小管超微结构变化、胶原 IV 和磷酸化 p38 的表达、ROS 产生、线粒体功能和细胞凋亡之间的关系。与表达对照水平 Mfn2 的糖尿病大鼠相比，内源性 Mfn2 的表达随时间而降低。与空白转染对照组相比，Mfn2 的过表达降低了肾脏相对于体重的重量，减少了蛋白尿和 ACR，并改善了糖尿病肾脏的典型病理变化，如肾小球增大、细胞外基质（ECM）积累和基底膜增厚。此外，Mfn2 的过表达抑制了 p38 的激活和 ROS 的积累；防止了线粒体功能障碍；减少了胶原 IV 的合成，但不影响肾脏细胞的凋亡。本研究表明，Mfn2 的过表达可以减轻糖尿病大鼠肾脏的病理变化。需要进一步研究来阐明这种保护作用的潜在机制。Mfn2 可能是治疗早期 DN 的潜在治疗靶点。
