Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy
Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy
复制标题
DOI：
10.1194/jlr.p040501
复制
发表时间：
2014-03-01
影响因子：
6.5
通讯作者：
Gafter, Uzi
中科院分区：
文献类型：
--
作者：
Herman-Edelstein, Michal;Scherzer, Pnina;Gafter, Uzi
动物模型将异位脂质积累与肾功能障碍联系起来，但这一过程是否发生在人类肾脏中尚不确定。为此，我们研究了肾脏TG和胆固醇代谢的改变是否会导致人类糖尿病肾病（DN）的脂质积累。对诊断为DN的患者（n = 34）的肾脏活检进行脂质染色和脂质代谢基因表达的研究，并与正常肾脏（n = 12）进行比较。我们观察到大量脂质沉积和细胞内脂滴增加。脂质沉积与脂质代谢基因失调有关。脂肪酸β -氧化途径包括ppar - α、肉毒碱棕榈酰转移酶1、酰基辅酶a氧化酶和L-FABP下调。肾脂蛋白脂肪酶（水解循环tg）的下调与血管生成素样蛋白4的表达增加有关。胆固醇摄取受体（包括LDL受体、氧化LDL受体和乙酰化LDL受体）表达显著增加，而影响胆固醇外排的基因（包括ABCA1、ABCG1和apoE）表达下调。肾小球滤过率、炎症和脂质代谢基因之间存在高度显著的相关性，支持脂质代谢异常在DN发病机制中的可能作用。这些数据表明，肾脏脂质代谢可以作为减缓肾小球硬化进展的特定治疗的靶点。
Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid beta-oxidation pathways including PPAR-alpha, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was down-regulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN.(jlr) These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis.