Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy
Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy
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DOI：
10.1097/01.asn.0000064292.37793.fb
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发表时间：
2003-05-01
影响因子：
13.6
通讯作者：
Eddy, AA
中科院分区：
文献类型：
--
作者：
Zhang, GQ;Kim, H;Eddy, AA
尿激酶细胞受体(UPAR)识别尿激酶型纤溶酶原激活物(UPA)的N-末端生长因子结构域，并由多种细胞表达。本研究旨在验证uPAR调节慢性损伤所致肾脏纤维化反应的假说。在单侧输尿管梗阻(UUO)或假手术后3~14d，观察uPAR野生型(+/+)和缺陷型(-/-)小鼠。在正常小鼠肾脏中未检测到uPAR基因的表达，在UUO后，uPAR基因在+/+小鼠中表达。原位杂交显示，梗阻大鼠肾小管和间质细胞中均有uPAR基因的转录。肾纤维化的严重程度，基于测量总胶原蛋白(第14天为13.5+/-1.5比9.8+/-1.0毫克/毫克肾；-/-比+/+)和马森三色染色的间质面积(22+/-4%比第14天的14+/-3%；-/-比+/+)在uPAR-/-小鼠中显著增加。在没有uPAR的情况下，UUO后第3天肾脏uPA活性显著低于野生型动物(UUO第3天62+/-20比135+/-13；UUO第7天74+/-17比141+/-16；UUO第14天98+/-20比165+/-10；-/-比+/+)。相反，调节纤溶酶活性的几个基因在两种基因型中的表达是相似的，包括uPA、tPA、PAI-1、蛋白酶Nexin-1和α2-抗纤溶酶。更糟糕的是，uPAR-/-小鼠的肾脏纤维化似乎不依赖于转化生长因子-β，因为-/-小鼠的转化生长因子-β活性实际上降低了65%，尽管肾脏转化生长因子-β1的信使核糖核酸水平相似。在uPAR-/-小鼠中，肝细胞生长因子(HGF)的主要2.3kb转录本和69kd活性蛋白的水平显著降低，这表明HGF和uPAR的肾脏保护作用之间存在潜在的联系。这些数据表明，肾脏uPAR减弱了对肾脏损伤的纤维化反应，这一结果部分是由尿激酶依赖但不依赖于纤溶酶原的功能介导的。
The urokinase cellular receptor (uPAR) recognizes the N-terminal growth factor domain of urokinase-type plasminogen activator (uPA) and is expressed by several cell types. The present study was designed to test the hypothesis that uPAR regulates the renal fibrogenic response to chronic injury. Groups of uPAR wild-type (+/+) and deficient (-/-) mice were investigated between 3 and 14 d after unilateral ureteral obstruction (UUO) or sham surgery. Not detected in normal kidneys, uPAR mRNA was expressed in response to UUO in the +/+ mice. By in situ hybridization, uPAR mRNA transcripts were detected in renal tubules and interstitial cells of the obstructed uPAR+/+ kidneys. The severity of renal fibrosis, based on the measurement of total collagen (13.5 +/- 1.5 versus 9.8 +/- 1.0 mug/mg kidney on day 14; -/- versus +/+) and interstitial area stained by Masson trichrome (22 +/- 4% versus 14 +/- 3% on day 14; -/- versus +/+) was significantly greater in the uPAR-/- mice. In the absence of uPAR, renal uPA activity was significantly decreased compared with the wild-type animals after UUO (62 +/- 20 versus 135 +/- 13 units at day 3 UUO; 74 +/- 17 versus 141 +/- 16 at day 7 UUO; 98 +/- 20 versus 165 +/- 10 at day 14 UUO; -/- versus +/+). In contrast, renal expression of several genes that regulate plasmin activity were similar in both genotypes, including uPA, tPA, PAI-1, protease nexin-1, and alpha2-antiplasmin. Worse renal fibrosis in the uPAR-/- mice appears to be TGF-beta-independent, as TGF-beta activity was actually reduced by 65% in the -/- mice despite similar renal TGF-beta1 mRNA levels. Significantly lower levels of the major 2.3-kb transcript and the 69-kd active protein of hepatocyte growth factor (HGF), a known anti-fibrotic growth factor, in the uPAR-/- mice suggests a potential link between HGF and the renoprotective effects of uPAR. These data suggest that renal uPAR attenuates the fibrogenic response to renal injury, an outcome that is mediated in part by urokinase-dependent but plasminogen-independent functions.