Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan,
Nephron. 2019;142(1):71-81. doi: 10.1159/000497325. Epub 2019 Feb 20.
BACKGROUND/AIMS: Calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus are immunosuppressants that are frequently used as "key drugs" in the fields of transplantation, steroid resistance, refractory nephrotic syndrome, and autoimmune disease. However, long-term CNI use causes nephrotoxicity, the features of which are arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, and focal segmental glomerulosclerosis (FSGS). We investigated whether FSGS in CNI-induced nephrotoxicity is associated with CD44-positive glomerular parietal epithelial cells (PECs), which play a significant role in experimental and human FSGS pathogenesis.
We utilized the mouse model of CsA-induced nephrotoxicity, as well as controls. Histopathological and functional data were sequentially collected from 1 to 25 weeks after CsA injection. Glomerular expression of CD44 was immunohistochemically evaluated, as were markers for glomerular podocytes and PECs.
Glomerular CD44 expression occurred from 2 weeks after CsA injection and gradually increased in the CsA group. CD44-positive glomerular cells showed coexpression of claudin-1 (PEC marker) but not of synaptopodin (podocyte marker). From 20 weeks after CsA injection, the cells formed a bridge between Bowman's capsule and the capillary tuft. These features are compatible with those of activated PECs, in which increased foot process effacement leads to bridge formation, and subsequently to an increase in glomerulosclerosis and a decrease in the expression of podocyte markers from 20 weeks.
CD44-positive (activated) PECs reflect extremely early podocyte injury in the progression of FSGS formation and may be a good marker for early detection of CNI-induced nephrotoxicity.
背景/目的：钙调神经磷酸酶抑制剂（CNIs）如环孢素 A（CsA）和他克莫司是免疫抑制剂，经常被用作移植、类固醇耐药、难治性肾病综合征和自身免疫性疾病等领域的“关键药物”。然而，长期使用 CNI 会导致肾毒性，其特征为细动脉玻璃样变、肾小管萎缩、条纹状间质纤维化和局灶节段性肾小球硬化（FSGS）。我们研究了 CNI 诱导的肾毒性中的 FSGS 是否与 CD44 阳性肾小球壁细胞上皮细胞（PEC）有关，后者在实验性和人类 FSGS 发病机制中起重要作用。
我们利用 CsA 诱导的肾毒性小鼠模型和对照组，从 CsA 注射后 1 至 25 周连续收集组织病理学和功能数据。通过免疫组织化学评估肾小球 CD44 的表达，以及肾小球足细胞和 PEC 的标志物。
肾小球 CD44 表达于 CsA 注射后 2 周开始出现，并在 CsA 组逐渐增加。CD44 阳性肾小球细胞同时表达 claudin-1（PEC 标志物）但不表达 synaptopodin（足细胞标志物）。从 CsA 注射后 20 周开始，这些细胞在鲍曼囊和毛细血管丛之间形成桥。这些特征与激活的 PEC 相符，其中足突融合导致桥形成，随后从 20 周开始 FSGS 形成增加，足细胞标志物表达减少。
CD44 阳性（激活）PEC 反映了 FSGS 形成过程中早期的足细胞损伤，可能是早期检测 CNI 诱导的肾毒性的良好标志物。
