Amelioration of progressive renal injury by genetic manipulation of Klotho gene
Amelioration of progressive renal injury by genetic manipulation of Klotho gene
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DOI：
10.1073/pnas.0611079104
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发表时间：
2007-02-13
影响因子：
11.1
通讯作者：
Kanwar, Yashpal S.
中科院分区：
文献类型：
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作者：
Haruna, Yoshisuke;Kashihara, Naoki;Kanwar, Yashpal S.
Klotho是一种器官分布受限的抗衰老基因，主要表达于肾小管；突变小鼠寿命缩短、动脉硬化、贫血和骨质疏松，这些都是慢性肾衰竭患者的常见特征。可以想象，Klotho基因表达的减少可能有助于肾衰竭的发展；或者，它的过表达可能导致icr源性肾小球肾炎（ICGN）小鼠模型中伴有微妙免疫复合物介导疾病的肾损伤的改善。为了解决这一问题，通过杂交产生了四种不同的小鼠品系：不含Klotho转基因的ICGN小鼠（ICGN）、含Klotho转基因的ICGN小鼠（ICGN/kITG）、含Klotho转基因的野生型小鼠（kITG）和不含Klotho转基因的野生型小鼠（对照）。40周龄时，ICGN小鼠的存活率约为30%，ICGN/kITG组的存活率约为70%。这种改善与肾功能、形态学病变和细胞色素c氧化酶活性的显著改善有关，但β -半乳糖苷酶活性（一种衰老相关蛋白）、线粒体DNA断裂、超氧阴离子产生、脂质过氧化、Bax蛋白表达和凋亡的减少有关。有趣的是，尽管Klotho仅局限于肾小管，但在肾小管和肾小球间室均有改善，这表明其基因产物具有显著的肾保护作用，可能作为一种循环激素，同时减轻线粒体氧化应激。
Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/kITG), wild-type mice with the Klotho transgene (kITG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was approximate to 30% in ICGN mice, and approximate to 70% in the ICGN/kITG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in beta-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.