Shankland S J, Hugo C, Coats S R, Nangaku M, Pichler R H, Gordon K L, Pippin J, Roberts J M, Couser W G, Johnson R J
Division of Nephrology, University of Washington, Seattle, USA.
Kidney Int. 1996 Oct;50(4):1230-9. doi: 10.1038/ki.1996.432.
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 in normal rats and rats with experimental mesangial proliferative glomerulonephritis (Thy1 model). Normal quiescent rat glomeruli have a differential expression for CKI's, where p27Kip1 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 p27Kip1 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 p27Kip1, while the expression for p21 increased substantially. Furthermore, mesangial cell p21 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.
系膜细胞损伤的一个典型反应是增殖，这与系膜基质积聚和肾小球疾病的进展密切相关。体外非肾细胞中的细胞增殖在细胞周期水平上由特定的细胞周期蛋白及其催化伙伴——细胞周期蛋白依赖性激酶（CDK）调节。细胞周期蛋白激酶抑制剂（CKI）通过抑制细胞周期进程来阻止增殖。然而，细胞周期调节蛋白在肾脏及肾脏疾病中的表达尚不清楚。为了确定这一点，我们研究了正常大鼠和实验性系膜增生性肾小球肾炎（Thy1模型）大鼠体内细胞周期蛋白的表达。正常静止的大鼠肾小球对CKI有差异表达，其中p27Kip1高表达，而p21（Cip1、Waf1、Sdi1、Cap20）（p21）水平较低。在Thy1肾小球肾炎中，当系膜细胞增殖达到最大值时，系膜细胞增殖的开始与p27Kip1水平的降低有关。体内系膜细胞增殖还与细胞周期蛋白A的肾小球表达增加以及CDK2的表达和活性增加有关。系膜细胞增殖的消退与p27Kip1恢复到基线水平有关，而p21的表达则大幅增加。此外，在增殖消退后，系膜细胞p21表达得以维持。这些结果为体内肾小球对损伤反应过程中细胞周期调节蛋白的复杂相互作用提供了证据。系膜细胞增殖期间CDK2表达的显著增加以及系膜细胞增殖消退后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描述的不同。
