Changes in cell-cycle protein expression during experimental mesangial proliferative glomerulonephritis
Changes in cell-cycle protein expression during experimental mesangial proliferative glomerulonephritis
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DOI：
10.1038/ki.1996.432
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发表时间：
1996-10-01
影响因子：
19.6
通讯作者：
Johnson, RJ
中科院分区：
文献类型：
--
作者：
Shankland, SJ;Hugo, C;Johnson, RJ
系膜细胞损伤的特征性反应是增殖，这与系膜基质积累和肾小球疾病的进展密切相关。体外非肾细胞的细胞增殖在细胞周期水平上受特定细胞周期蛋白及其催化伙伴细胞周期蛋白依赖性激酶（CDK）的调控。细胞周期蛋白激酶抑制剂（CKI）通过抑制细胞周期进程来防止细胞增殖。然而，细胞周期调节蛋白在肾脏和肾脏疾病中的表达尚不清楚。为此，我们研究了正常大鼠和实验性系膜增殖性肾小球肾炎（Thy1模型）大鼠体内细胞周期蛋白的表达。正常静止大鼠肾小球对CKI有不同的表达，其中p27（Kip1）高表达，而p21 (Cip1, Waf1, Sdi1, Cap20) （p21）水平低。Thy1型肾小球肾炎患者系膜细胞增殖的发生与系膜细胞增殖最剧烈时p27（Kip1）水平降低有关。体内系膜细胞的增殖也与肾小球细胞周期蛋白A表达的增加以及CDK2表达和活性的增加有关。系膜细胞增殖的消退与p22（Kip1）恢复到基线水平相关，而在增殖消退后，p22的表达保持不变。这些结果为细胞周期调节蛋白在体内对损伤的肾小球反应中复杂的相互作用提供了证据。系膜细胞增殖过程中CDK2表达的显著增加以及系膜细胞增殖结束后p21表达的持续增加表明，某些细胞周期蛋白的体内表达可能与体外非肾细胞中的表达不同。
A characteristic response to mesangial cell injury is proliferation, which is closely linked to mesangial matrix accumulation and the progression of glomerular disease. Cell proliferation in non-renal cells in vitro is regulated at the level of the cell-cycle by specific cyclins and their catalytic partners, cyclin dependent kinases (CDK). Cyclin kinase inhibitors (CKI) prevent proliferation by inhibiting cell-cycle progression. However, the expression of cell-cycle regulatory proteins in the kidney and in renal disease is unknown. To determine this we studied the expression of cell-cycle proteins in vivo normal rats and rats with experimental mesangial proliferative glomerulonephritis (Thy1 model). Normal quiescent rat glomeruli have a different expression for CKI's, where p27(Kip1) is highly expressed, and the levels for p21 (Cip1, Waf1, Sdi1, Cap20) (p21) are low. The onset of mesangial cell proliferation in Thy1 glomerulonephritis is associated with a reduction in p27(Kip1) levels when mesangial cell proliferation is maximal. Mesangial cell proliferation in vivo is also associated with an increase in glomerular expression of cyclin A, and an increase in expression and activity for CDK2. The resolution of mesangial cell proliferation was associated with a return to baseline levels for p22(Kip1), while the expression was maintained following the resolution of proliferation. These results provide evidence for a complex interplay of cell-cycle regulatory proteins during the glomerular response to injury in vivo. The marked increase in CDK2 expression during mesangial cell proliferation and the sustained increase in p21 expression following the resolution of mesangial cell proliferation suggests that the in vivo expression of certain cell-cycle proteins may differ from that described in non-renal cells in vitro.