Shinosaki Toshihiro, Notoya Mitsuru, Nomura Yasuharu, Miyai Ikuko, Kobayashi Tatsuo, Kurihara Hidetake
Shionogi Discovery Research Laboratories, Shionogi & Co., Toyonaka, Osaka, Japan.
Exp Nephrol. 2002;10(4):245-58. doi: 10.1159/000063699.
Anti-Thy-1.1 antibody induces mesangioproliferative glomerulonephritis; however, the mesangial lesion is spontaneously recovered to the normal feature. Glomerular epithelial cells (GECs) play a crucial role in the glomerular function. Very little is known about the involvement of GECs in this disease model. This study is designed to investigate whether GEC injury prolongs the mesangial lesion.
The effects of GEC damage on mesangioproliferative nephritis were studied with combined treatment using puromycin aminonucleoside (PAN) and monoclonal antibody (MAb) against rat mesangial Thy-1.1. Urinary protein, BUN, Pcr and Ccr were measured. To clarify the underlying mechanisms, morphological study and immunohistochemistry for alpha-SMA, FGF-2 and PCNA were carried out.
Simultaneous administration of PAN plus MAb induced progressive mesangioproliferative nephritis compared to PAN or MAb alone. Rats with combined treatment displayed renal dysfunction with massive proteinuria. Morphological studies showed that the glomeruli in combined group had features resembling those of progressive mesangial proliferative glomerulonephritis in humans. Morphologic lesions of GECs in acute nephritic phase were severer than those in other groups. Immunohistochemistry revealed that glomeruli of combined treatment exhibited persistent overexpression of alpha-SMA and FGF-2.
Simultaneous dysfunction of GECs and mesangial cells can lead to persistent glomerular perturbations with prolonged phenotypic change of mesangial cells, resulting in end-stage renal deficiency. GEC damage during the acute nephritic phase contributes to the progression of irreversible renal disease.
抗Thy-1.1抗体可诱发系膜增生性肾小球肾炎；然而，系膜病变可自发恢复至正常状态。肾小球上皮细胞（GECs）在肾小球功能中起关键作用。关于GECs在该疾病模型中的作用知之甚少。本研究旨在探讨GEC损伤是否会延长系膜病变。
采用嘌呤霉素氨基核苷（PAN）和抗大鼠系膜Thy-1.1单克隆抗体（MAb）联合治疗，研究GEC损伤对系膜增生性肾炎的影响。检测尿蛋白、血尿素氮、肌酐清除率和肌酐。为阐明潜在机制，进行了形态学研究以及α-SMA、FGF-2和PCNA的免疫组化检测。
与单独使用PAN或MAb相比，同时给予PAN加MAb可诱发进行性系膜增生性肾炎。联合治疗的大鼠出现肾功能障碍并伴有大量蛋白尿。形态学研究表明，联合组的肾小球具有类似于人类进行性系膜增生性肾小球肾炎的特征。急性肾炎阶段GECs的形态学损伤比其他组更严重。免疫组化显示，联合治疗组的肾小球表现出α-SMA和FGF-2的持续过度表达。
GECs和系膜细胞同时功能障碍可导致肾小球持续紊乱，系膜细胞表型改变延长，从而导致终末期肾功能不全。急性肾炎阶段的GEC损伤促使不可逆性肾脏疾病进展。
