Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats
Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats
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DOI：
10.1038/ki.1996.95
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发表时间：
1996-03-01
影响因子：
19.6
通讯作者：
Floege, J
中科院分区：
文献类型：
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作者：
Kliem, V;Johnson, RJ;Floege, J
5/6肾切除模型用于研究慢性肾功能衰竭的发病机制。我们以前证明，在这个模型中，肾小球硬化发生前肾小球系膜细胞增殖和肾小球PDGF B链表达增加。在本研究中，我们已经评估了皮质tubuloacettium的伴随变化。5/6肾切除术后第1周出现肾小管和间质细胞增殖波（通过PCNA免疫染色确定）。该波先于肾小球细胞增殖峰值一周。此后肾小管间质细胞增殖降低，并在第10周达到对照值。在假手术对照组中，PDGF B链和β受体的原位杂交和免疫染色显示远端小管和集合管的标记，而回肠中不存在信号。5/6肾切除术后第2周和第4周，肾小管中PDGF B链mRNA和蛋白表达显著增加，第2周至第10周，肾小管中PDGF B链mRNA和蛋白表达显著增加（特别是在炎性浸润区域）。PDGF受体β亚单位免疫染色也发生了类似的变化。第1周后，结蛋白和α-平滑肌肌动蛋白（肌成纤维细胞的标志物）的间质表达逐渐增加。单核细胞/巨噬细胞的间质内流伴局灶性加重开始于第2周。淋巴细胞、中性粒细胞和血小板计数仅显示微小变化。与单核细胞/巨噬细胞流入平行，胶原蛋白I和IV、层粘连蛋白和纤连蛋白发生进行性间质蓄积。所有这些变化与血清肌酐、蛋白尿和肾小管间质损伤指数的增加相关。我们的结论是，肾小管间质的变化后，5/6肾切除术表现出相似之处，在肾小球中观察到的。PDGF B链及其受体在肾小管和间质中的过度表达可能在介导肾小管间质损伤区域的成纤维细胞迁移和/或增殖中起作用。
The 5/6 nephrectomy model is used to study pathogenetic mechanisms underlying chronic renal failure. We previously demonstrated that increased mesangial cell proliferation and glomerular PDGF B-chain expression precede glomerulosclerosis in this model. In the present study we have assessed the concomitant changes in the cortical tubulointerstitium. A wave of tubular and interstitial cell proliferation (as determined by immunostaining for PCNA) occurred at week 1 after 5/6 nephrectomy. This wave preceded the peak glomerular cell proliferation by one week. Tubulointerstitial cell proliferation decreased thereafter and reached control values by week 10. in situ hybridization and immunostaining for PDGF B-chain and beta-receptor in sham-operated controls showed labeling of distal tubules and collecting ducts, while no signal was present in the interstitium. PDGF B-chain mRNA and protein expression was markedly increased in tubules at weeks 2 and 4 after 5/6 nephrectomy and in the interstitium (particularly in areas of inflammatory infiltrates) at weeks 2 to 10. Similar changes occurred with PDGF receptor beta-subunit immunostaining. Interstitial expression of desmin and of alpha-smooth muscle actin (markers of myofibroblasts) progressively increased after week 1. Interstitial influx of monocytes/macrophages with focal accentuation started at week 2. Counts of lymphocytes, neutrophils and platelets showed only minor changes. In parallel to the monocyte/macrophage influx, progressive interstitial accumulation of collagens I and IV, laminin, and fibronectin occurred. All of these changes were correlated with the increase in serum creatinine, proteinuria and an index of tubulointerstitial damage. We conclude that tubulointerstitial changes after 5/6 nephrectomy show similarities with those observed in the glomeruli. Tubular and interstitial overexpression of PDGF B-chain and its receptor may play a role in mediating fibroblast migration and/or proliferation in areas of tubulointerstitial injury.