PDF(Pubmed)
Abstract：
ATP6AP2 knockout in the renal nephron impairs receptor-mediated endocytosis, increasing urinary albumin and glucose excretion and impairing weight gain. Nonesterified fatty acids (NEFA) in urine are bound to albumin and reabsorbed in the proximal tubule through receptor-mediated endocytosis by the megalin-cubilin complex. We hypothesized that ATP6AP2 knockout increases urinary NEFA excretion through a reduction in megalin. Ten-week-old male C57BL/6 mice with nephron specific inducible ATP6AP2 knockout and noninduced controls were fed either normal diet (ND 12% fat) or high fat diet (HFD 45% fat) for 6 months. ATP6AP2 knockout significantly increased urine albumin:creatinine ratio in both ND and HFD fed mice while normalized urine NEFA concentration increased 489% and 259% in ND and HFD knockout mice compared to respective controls. Knockout decreased renal cortical megalin mRNA by 47% on ND and 49% on HFD while megalin protein expression decreased by 36% and 44% respectively. At the same time, markers of mTOR activity were increased while autophagy was impaired. Our results indicate that nephron specific ATP6AP2 knockout increases urinary NEFA excretion in the setting of impaired receptor-mediated endocytosis. Further investigation should determine whether ATP6AP2 contributes to obesity related ectopic lipid deposition in the proximal tubule.
摘要：
肾肾单位中的ATP6AP2敲除会损害受体介导的内吞作用，增加尿白蛋白和葡萄糖排泄并损害体重增加。尿液中的非酯化脂肪酸（NEFA）与白蛋白结合，并通过megalin-cubilin复合物通过受体介导的内吞作用在近端小管中重新吸收。我们假设ATP6AP2敲除通过减少megalin增加尿NEFA排泄。对具有肾单位特异性诱导型ATP6AP2敲除和非诱导对照的10周龄雄性C57BL/6小鼠饲喂正常饮食(ND12%脂肪)或高脂肪饮食(HFD45%脂肪)6个月。ATP6AP2敲除显著增加ND和HFD饲喂小鼠的尿白蛋白:肌酸酐比率,而与各自的对照相比,ND和HFD敲除小鼠的归一化尿NEFA浓度增加489%和259%。敲除使ND和HFD的肾皮质megalinmRNA降低了47％，而megalin蛋白表达分别降低了36％和44％。同时,mTOR活性标志物增加,自噬受损.我们的结果表明，在受体介导的内吞作用受损的情况下，肾单位特异性ATP6AP2敲除会增加尿NEFA的排泄。进一步的研究应确定ATP6AP2是否有助于近端小管中肥胖相关的异位脂质沉积。
