Kriz Wilhelm, Hartmann Ingrid, Hosser Hiltraud, Hähnel Brunhilde, Kränzlin Bettina, Provoost Abaraham P, Gretz Norbert
Institut für Anatomie und Zellbiologie, Universität Heidelberg, Heidelberg, Germany.
Zentrum für Medizinische Forschung, Universitätsklinikum Mannheim der Universität Heidelberg, Mannheim, Germany.
J Am Soc Nephrol. 2001 Mar;12(3):496-506. doi: 10.1681/ASN.V123496.
In two genetic models of "classic" focal segmental glomerulosclerosis (FSGS), the Milan normotensive and the Fawn-hooded hypertensive rats, tracer studies were performed to test the hypothesis that misdirected glomerular filtration and peritubular filtrate spreading are relevant mechanisms that contribute to nephron degeneration in this disease. Two exogenous tracers, lissamine green and horse spleen ferritin, were administered by intravenous injection and subsequently traced histologically in serial kidney sections. In contrast to control rats, both tracers in kidneys of Milan normotensive and Fawn-hooded hypertensive rats with established FSGS were found to accumulate extracellularly at the following sites: (1) within tuft adhesions to Bowman's capsule and associated paraglomerular spaces, (2) at the glomerulotubular junction contained within extensions of the paraglomerular spaces onto the tubule, and (3) within subepithelial peritubular spaces eventually encircling the entire proximal convolution of an affected nephron. This distribution strongly suggests the existence of misdirected filtration into tuft adhesions to Bowman's capsule and subsequent spreading of the filtrate around the entire circumference of a glomerulus and, alongside the glomerulotubular junction, onto the outer aspect of the corresponding tubule. This leads to an interstitial response that consists of the formation of a barrier of sheet-like fibroblast processes around the affected nephron, which confines the filtrate spreading and, subsequently, the destructive process to the affected nephron. No evidence was found that either misdirected filtration and peritubular filtrate spreading themselves or the associated tubulo-interstitial process led to the transfer of the injury from an affected nephron to an unaffected nephron. It is concluded that in the context of FSGS development, misdirected filtration and peritubular filtrate spreading are important damaging mechanisms that underlie the extension of glomerular injury to the corresponding tubulointerstitium, thus leading finally to degeneration of both the glomerulus and the tubule of a severely injured nephron.
在“经典”局灶节段性肾小球硬化（FSGS）的两种遗传模型——米兰正常血压大鼠和鹿鼠高血压大鼠中，进行了示踪研究，以检验以下假说：肾小球滤过方向错误和肾小管周围滤液扩散是导致该疾病肾单位退化的相关机制。通过静脉注射给予两种外源性示踪剂——丽丝胺绿和马脾铁蛋白，随后在肾脏连续切片中进行组织学追踪。与对照大鼠相比，在已患FSGS的米兰正常血压大鼠和鹿鼠高血压大鼠的肾脏中，两种示踪剂均在以下部位细胞外积聚：（1）在与鲍曼囊的肾小球粘连及相关肾小球旁间隙内；（2）在肾小球旁间隙延伸至肾小管上的肾小球肾小管连接处；（3）在肾小管上皮下间隙内，最终环绕受影响肾单位的整个近端曲管。这种分布强烈提示存在滤过方向错误进入与鲍曼囊的肾小球粘连，随后滤液在肾小球整个圆周周围扩散，并沿着肾小球肾小管连接处扩散到相应肾小管的外侧。这导致一种间质反应，即围绕受影响肾单位形成由片状成纤维细胞突起构成的屏障，该屏障限制滤液扩散，进而将破坏过程局限于受影响的肾单位。未发现证据表明滤过方向错误和肾小管周围滤液扩散本身或相关的肾小管间质过程会导致损伤从受影响的肾单位转移至未受影响的肾单位。得出的结论是，在FSGS发展过程中，滤过方向错误和肾小管周围滤液扩散是重要的损伤机制，是肾小球损伤扩展至相应肾小管间质的基础，最终导致严重受损肾单位的肾小球和肾小管均发生退化。
