Departmentsof Clinical Science, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden. fredrik.duner @ ki.se
Nephron Exp Nephrol. 2010;116(2):e42-52. doi: 10.1159/000317130. Epub 2010 Jun 29.
BACKGROUND/AIMS: It is still unclear what happens in the glomerulus when proteinuria starts. Using puromycin aminonucleoside nephrosis (PAN) rats, we studied early ultrastructural and permeability changes in relation to the expression of the podocyte-associated molecules nephrin, α-actinin, dendrin, and plekhh2, the last two of which were only recently discovered in podocytes.
Using immune stainings, semiquantitative measurement was performed under the electron microscope. Permeability was assessed using isolated kidney perfusion with tracers. Possible effects of ACE inhibition were tested.
By day 2, some patchy foot process effacement, but no proteinuria, appeared. The amount of nephrin was reduced in both diseased and normal areas. The other proteins showed few changes, which were limited to diseased areas. By day 4, foot process effacement was complete and proteinuria appeared in parallel with signs of size barrier damage. Nephrin decreased further, while dendrin and plekhh2 also decreased but α-actinin remained unchanged. ACE inhibition had no significant protective effect.
PAN glomeruli already showed significant pathology by day 4, despite relatively mild proteinuria. This was preceded by altered nephrin expression, supporting its pivotal role in podocyte morphology. The novel proteins dendrin and plekhh2 were both reduced, suggesting roles in PAN, whereas α-actinin was unchanged.
背景/目的：蛋白尿起始时肾小球内发生的情况尚不清楚。本研究使用嘌呤霉素氨基核苷肾病（PAN）大鼠，研究了与足细胞相关分子nephrin、α-辅肌动蛋白、dendrin 和 plekhh2 表达相关的早期超微结构和通透性变化，后两者是最近才在足细胞中发现的。
采用免疫染色法，在电子显微镜下进行半定量测量。通过分离肾灌注示踪剂评估通透性。测试了 ACE 抑制的可能作用。
第 2 天，出现了一些局灶性足突融合，但没有蛋白尿。nephrin 在病变和正常区域的含量均减少。其他蛋白的变化较少，仅限于病变区域。第 4 天，足突完全融合，蛋白尿与大小屏障损伤的迹象同时出现。nephrin 进一步减少，而 dendrin 和 plekhh2 也减少，但 α-辅肌动蛋白保持不变。ACE 抑制没有明显的保护作用。
尽管蛋白尿相对较轻，但 PAN 肾小球在第 4 天已经表现出明显的病理学改变。这之前是 nephrin 表达的改变，支持其在足细胞形态中的关键作用。新发现的蛋白 dendrin 和 plekhh2 均减少，提示其在 PAN 中发挥作用，而α-辅肌动蛋白不变。
