Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Research Program in Mitochondrial Therapeutics, Weill Cornell Medical College, New York, New York, USA.
Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Research Program in Mitochondrial Therapeutics, Weill Cornell Medical College, New York, New York, USA.
Kidney Int. 2016 Nov;90(5):997-1011. doi: 10.1016/j.kint.2016.06.013. Epub 2016 Aug 9.
Obesity is a major risk factor for the development of chronic kidney disease, even independent of its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding of obesity-related kidney disease is glomerulopathy, with glomerular hypertrophy, mesangial matrix expansion, and focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition of AMP kinase, and endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure in glomerular endothelial cells, podocytes, and proximal tubular epithelial cells after 28 weeks of a high-fat diet in C57BL/6 mice. Treatment with SS-31, a tetrapeptide that targets cardiolipin and protects mitochondrial cristae structure, during high-fat diet preserved normal mitochondrial structure in all kidney cells, restored renal AMP kinase activity, and prevented intracellular lipid accumulation, endoplasmic reticulum stress, and apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, SS-31 prevented loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-β) cytokines. Thus, mitochondria protection can overcome lipotoxicity in the kidney and represent a novel upstream target for therapeutic development.
肥胖是慢性肾脏病发展的一个主要危险因素，即使它与高血压、糖尿病和血脂异常无关。肥胖相关肾病的主要病理发现是肾小球病，伴有肾小球肥大、系膜基质扩张和局灶节段性肾小球硬化。导致肾脏病理的机制包括异常脂质代谢、脂毒性、AMP 激酶抑制和内质网应激。在这里，我们报告了在 C57BL/6 小鼠高脂肪饮食 28 周后肾小球内皮细胞、足细胞和近端肾小管上皮细胞中线粒体结构的显著变化。在高脂肪饮食期间，用靶向心磷脂并保护线粒体嵴结构的四肽 SS-31 治疗可保持所有肾脏细胞的正常线粒体结构，恢复肾脏 AMP 激酶活性，并防止细胞内脂质积累、内质网应激和细胞凋亡。SS-31 对体重增加、胰岛素抵抗或高血糖没有影响。然而，SS-31 可防止肾小球内皮细胞和足细胞、系膜扩张、肾小球硬化、巨噬细胞浸润以及促炎（TNF-α、MCP-1、NF-κB）和促纤维化（TGF-β）细胞因子的上调。因此，线粒体保护可以克服肾脏的脂毒性，代表治疗开发的一个新的上游靶点。
