Diabetic nephropathy (DN) is associated with renal mitochondrial injury and decreased renal klotho expression. Klotho is known as an aging suppressor, and mitochondrial dysfunction is the hallmark of aging. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a master regulator of mitochondrial biogenesis, and adenosine monophosphate-activated protein kinase (AMPK) is known as a guardian of mitochondria. Here, we report that recombinant soluble klotho protein (rKL) protects against DN in db/db mice via PGC1α-AMPK-mediated mitochondrial recovery in the kidney. We injected rKL into db/db and db/m mice for 8 weeks and collected the serum and kidney tissue. We treated murine renal tubular cells with rKL in vitro, with and without exposure to 30 mM high glucose (HG). rKL treatment ameliorated major disorders from diabetes, such as obesity, hyperglycemia, and intrarenal reactive oxygen species (ROS) generation, in db/db mice. rKL also diminished albuminuria, recovered renal proximal tubular mitochondria, increased renal p-AMPK and PGC1α, and down-regulated mTOR/TGF-β in db/db mice. In S1 mouse proximal tubular cells, rKL treatment ameliorated HG-mediated cellular and mitochondrial damage and enhanced oxidative phosphorylation, with an increase in PGC1α-AMPK-induced mitochondrial recovery. Our data suggest that klotho exerts a mitochondrial protective effect in diabetic kidney disease by inducing AMPK-PGC1α expression.

糖尿病肾病（DN）与肾线粒体损伤和肾klotho表达降低有关。Klotho被称为衰老抑制剂，线粒体功能障碍是衰老的标志。过氧化物酶体增殖物激活受体γ辅激活物1-alpha（PGC1α）是线粒体生物发生的主要调节剂，而腺苷单磷酸激活蛋白激酶（AMPK）被称为线粒体的守护者。在这里，我们报道重组可溶性klotho蛋白（rKL）通过PGC1α-AMPK介导的肾脏线粒体恢复，保护了db / db小鼠中的DN。我们将rKL注射到db / db和db / m小鼠中8周，并收集血清和肾脏组织。我们用rKL体外处理了鼠肾小管细胞，无论是否暴露于30 mM高血糖（HG）。rKL治疗改善了db / db小鼠的糖尿病引起的主要疾病，例如肥胖，高血糖和肾内活性氧（ROS）生成。rKL还可以减少蛋白尿，恢复肾近端肾小管线粒体，增加肾p-AMPK和PGC1α并降低db / db小鼠的mTOR /TGF-β。在S1小鼠近端肾小管细胞中，rKL治疗改善了HG介导的细胞和线粒体损伤并增强了氧化磷酸化作用，并增加了PGC1α-AMPK诱导的线粒体恢复。我们的数据表明，klotho通过诱导AMPK-PGC1α表达在糖尿病肾病中发挥线粒体保护作用。