Second Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University ofToyama, and Fujikoshi Hospital, 2630, Sugitani, Toyama 930-0194, Japan.
Nephrol Dial Transplant. 2011 Feb;26(2):458-68. doi: 10.1093/ndt/gfq468. Epub 2010 Aug 5.
Mesangial cell functions are critically regulated by platelet-derived growth factor receptor (PDGFR)-β signals. In contrast to the well-established role of PDGFR-β in the development of kidney glomerulus, its role in adult kidney glomerulus remains controversial.
We deleted the PDGFR-β gene postnatally using the Cre-loxP system and analysed the long-term effects of PDGFR-β inhibition on glomerular changes associated with ageing and subtotal nephrectomy.
Mice depleted of PDGFR-β (Deletant) survived without showing apparent abnormalities. In glomerulus of Deletant, mesangial PDGFR-β expression was decreased. The glomerular cell numbers were low, and the ageing-associated increment of mesangial matrix area was suppressed in Deletant as compared with control mice with conserved PDGFR-β expression (Floxed) at 48 weeks of age. At 2 weeks after subtotal nephrectomy, albuminuria and the elevation of blood urea nitrogen were aggravated in Deletant. At this time, Deletant showed specific glomerular changes that included many hypertrophic podocytes and collapsed capillaries. At 12 weeks after subtotal nephrectomy, the kidney function in Deletant restored to the level of Floxed; however, the Deletant glomeruli showed dilated capillaries, decreased cell number and reduced mesangial matrix area with less extended mesangial cell processes as compared with Floxed.
The long-term inhibition of mesangial PDGFR-β prevented age-related mesangial expansion. On the other hand, the kidney glomeruli with decreased PDGFR-β showed increased vulnerability to the acute nephron loss, and showed mesangial insufficiency in the following adaptive process.
血小板衍生生长因子受体 (PDGFR)-β 信号对系膜细胞功能具有关键的调节作用。与 PDGFR-β 在肾脏肾小球发育中的作用已得到充分证实相反，其在成年肾脏肾小球中的作用仍存在争议。
我们利用 Cre-loxP 系统在出生后敲除 PDGFR-β 基因，并分析 PDGFR-β 抑制对与年龄增长和部分肾切除相关的肾小球变化的长期影响。
缺乏 PDGFR-β 的小鼠（敲除鼠）在没有明显异常的情况下存活。在敲除鼠的肾小球中，系膜 PDGFR-β 表达减少。与表达 PDGFR-β 的对照小鼠（Floxed）相比，敲除鼠的肾小球细胞数量较低，与年龄相关的系膜基质面积增加受到抑制，这些小鼠在 48 周龄时被观察到。在部分肾切除后 2 周，敲除鼠的蛋白尿和血尿素氮升高加剧。此时，敲除鼠表现出特定的肾小球变化，包括许多肥大的足细胞和塌陷的毛细血管。在部分肾切除后 12 周，敲除鼠的肾功能恢复到 Floxed 水平；然而，与 Floxed 相比，敲除鼠的肾小球显示出扩张的毛细血管、细胞数量减少和系膜基质面积减少，系膜细胞突起较少延伸。
长期抑制系膜 PDGFR-β 可防止与年龄相关的系膜扩张。另一方面，PDGFR-β 减少的肾小球对急性肾单位丢失的敏感性增加，并且在随后的适应过程中表现出系膜功能不全。
