He Xiao-jie, Yi Zhu-wen, Dang Xi-qiang, Zhang Hui-qiong, He Qing-nan, Mo Shuang-hong, Bai Hai-tao, Geng Wen-mao, Yang Hua-bin
Laboratory of Pediatric Nephrology, The Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Hunan Province Clinical Center of Pediatric Nephrology, Changsha 410011, China.
Zhonghua Er Ke Za Zhi. 2005 Feb;43(2):109-12.
Glucocorticoid (GC) is the first therapeutic choice of primary nephrotic syndrome (PNS). The response to GC treatment is an important indicator for the outcome of PNS children. Children with GC-resistant PNS present with incomplete or no response to GC, and may herald the progression to end-stage renal failure. However, the detailed mechanism of GC-resistance or GC-sensitive effect in these PNS children has not been clearly elucidated. The previous study by the authors indicated that there was increased expression of GR beta in PBMCs in GC-resistant children with PNS, and the over expression of GR beta resulted in GC resistance via influencing the ability of GR alpha nuclear translocation. To elucidate the relationship between GR beta expression in renal and in PBMCs and the effect of glucocorticoid on glucocorticoid-resistance children with PNS, the expression of GR alpha and GR beta in renal tissue and in PBMCs were detected by immunohistochemistry.
Forty children with PNS were divided into two groups, GC-resistant group(20) and GC-sensitive group(20), the expression of GR alpha and GR beta in renal intrinsic cells and in PBMCs were measured with the immunohistochemistry technique. A semiquantitative score was used to evaluate the injury degree of the glomeruli and tubulointerstitium.
Compared with GC-sensitive group, the glomerular pathologic scores (6.91 +/- 1.98) and renal tubular pathologic scores (7.12 +/- 1.62) in GC- resistant group were significantly different (P < 0.01, respectively). GR alpha expressions of renal tissue and PBMCs were higher in the control group (58.3 +/- 2.6, 59.1 +/- 7.2) than those in the GC-sensitive group (40.2 +/- 7.2 and 36.6 +/- 5.1, P < 0.01, respectively) and GC-resistant group (35.0 +/- 8.2 and 36.4 +/- 6.6, P < 0.01, respectively). GR beta expressions of renal tissue and PBMCs were higher in the GC-resistant group (13.8 +/- 3.0 and 12.1 +/- 4.1) and in the GC-sensitive group (6.5 +/- 1.9 and 5.9 +/- 1.0) than that in control group (2.3 +/- 0.4 and 3.2 +/- 1.1, P < 0.01, respectively). GR beta expressions in renal tissue and PBMCs were higher in the GC-resistant group than that in the GC-sensitive group (P < 0.01). Compared with control group, GR beta expressions in PBMCs and in renal tissue were lower than those in mild renal lesion group (5.4 +/- 2.8, 6.46 +/- 2.50), midmedium renal lesion group (8.7 +/- 2.4 and 11.4 +/- 3.7) and (17.1 +/- 0.4 and 18.7 +/- 0.7) in severe renal lesion group (F = 5.8, 15.6, P < 0.01, respectively). GR beta expression of PBMCs had a positive correlation with GR beta expression of renal intrinsic cells (r = 0.651, P < 0.01). GR beta expressions by PBMCs and renal intrinsic cells were positively correlated with renal pathologic scores (r = 0.579 and 0.623, P < 0.01, respectively).
GC-resistant children with PNS were related to the increased GR beta expression in PBMCs and renal intrinsic cells. There was no correlation between the GR alpha expressions in PBMCs and in renal intrinsic cells. Increased GR beta expression might decrease the effect of GC via inhibiting the activity of GR alpha.
糖皮质激素（GC）是原发性肾病综合征（PNS）的首选治疗药物。GC治疗反应是PNS患儿预后的重要指标。GC抵抗型PNS患儿对GC治疗反应不完全或无反应，可能预示着进展至终末期肾衰竭。然而，这些PNS患儿中GC抵抗或GC敏感效应的详细机制尚未明确阐明。作者之前的研究表明，GC抵抗型PNS患儿外周血单个核细胞（PBMCs）中糖皮质激素受体β（GRβ）表达增加，GRβ的过表达通过影响GRα核转位能力导致GC抵抗。为阐明肾组织和PBMCs中GRβ表达与糖皮质激素对GC抵抗型PNS患儿的作用之间的关系，采用免疫组织化学法检测肾组织和PBMCs中GRα和GRβ的表达。
40例PNS患儿分为两组，GC抵抗组（20例）和GC敏感组（20例），采用免疫组织化学技术检测肾固有细胞和PBMCs中GRα和GRβ的表达。采用半定量评分评估肾小球和肾小管间质的损伤程度。
与GC敏感组相比，GC抵抗组的肾小球病理评分（6.91±1.98）和肾小管病理评分（7.12±1.62）有显著差异（P均<0.01）。对照组肾组织和PBMCs中GRα表达（分别为58.3±2.6、59.1±7.2）高于GC敏感组（分别为40.2±7.2和36.6±5.1，P均<0.01）和GC抵抗组（分别为35.0±8.2和36.4±6.6，P均<0.01）。GC抵抗组和GC敏感组肾组织和PBMCs中GRβ表达（分别为13.8±3.0和12.1±4.1、6.5±1.9和5.9±1.0）高于对照组（分别为2.3±0.4和3.2±1.1，P均<0.01）。GC抵抗组肾组织和PBMCs中GRβ表达高于GC敏感组（P<0.01）。与对照组相比，PBMCs和肾组织中GRβ表达低于轻度肾病变组（分别为5.4±2.8、6.46±2.50）、中度肾病变组（分别为8.7±2.4和11.4±3.7）和重度肾病变组（分别为17.1±0.4和18.7±0.7）（F分别为5.8、15.6，P均<0.01）。PBMCs中GRβ表达与肾固有细胞中GRβ表达呈正相关（r=0.651，P<0.01）。PBMCs和肾固有细胞中GRβ表达与肾病理评分呈正相关（r分别为0.579和0.623，P均<0.01）。
GC抵抗型PNS患儿与PBMCs和肾固有细胞中GRβ表达增加有关。PBMCs和肾固有细胞中GRα表达之间无相关性。GRβ表达增加可能通过抑制GRα活性降低GC的作用。
