成纤维细胞生长因子受体4在人发育肾和病理肾中的表达

Expression of fibroblast growth factor receptor-4 in fetal kidneys and pathological kidneys of children

目的观察成纤维细胞生长因子受体4（Fibroblast growth factor receptor4，FGFR4）在人发育肾组织和儿童常见肾脏疾病中的表达，研究成纤维细胞生长因子（Fibroblast growth factor，FGF）及其受体（FGFR4）在人发育肾和病理肾中的作用，为肾脏病理发生机制研究提供新思路。方法采用免疫组化法分析FGFR4在18例8～34周龄胎儿肾组织和82例儿科常见肾脏疾病，包括原发性肾病综合征、急性肾炎、紫癜性肾炎、单纯性血尿的表达，并作与肾脏病理积分的相关性分析。结果①肾发生带内FGFR4表达微弱，肾囊泡和S型小体的上支和中间支，即原始肾小管上皮细胞部位有微弱表达，间充质、压缩间充质细胞未见表达，输尿管芽及其末端壶腹和C-期足细胞表达不明显。M-期肾小球和近端小管无阳性细胞染色，远端小管和集合管表达较为明显。②所有病理切片均存在FGFR4不同程度阳性的表达，较正常对照组明显增加，其中肾小球区表达微弱，主要在足细胞部位；肾小管区表达较为强烈，主要部位在远端小管，表达密集部位的小管结构明显异常，表现为细胞萎缩、管腔扩大，尤其部分近端小管更为明显。③原发性肾病综合征与其他3种肾脏疾病的各部位FGFR4表达均未见明显差异（P〉0．05）。肾近端小管和远端小管各病理类型间FGFR4表达差异无显著性，足细胞FGFR4表达在紫癜性肾炎组明显高于其他各病理类型组（P〈0．05）。④相关性分析发现，近端小管FGFR4表达与肾小管病理积分呈正相关，其他各部位表达均与病理积分呈负相关（均P〈0．05）。结论FGF-FGFR4对早期肾单位的形成可能不起关键作用，而是与其后期较成熟阶段肾小管和集合管发育的调控有关。FGFR4可能参与儿童原发性肾病综合征、急性肾炎、紫癜性肾炎、单纯性血尿的病理发生，表达程度增多与肾脏病理损害有一定关系，表达适度增多有利于足细胞和肾小管损伤修复，过表达则可能加重病理损害。

Objective To investigate the expression of fibroblast growth factor receptor-4 （FGFR4） in fetal kidneys and pathological kidneys of children in order to show the roles of fibroblast growth factor （FGF） and FGFR4 in the development of fetal kidneys and renal diseases. Methods The expression of FGFR4 was detected by immumohistochemistry in the normal fetal kidney at 8 to 34 weeks of gestation age （ n = 18 ） and 82 children with renal disease, including 28 cases of primary nephrotic syndrome （PNS）, 12 acute glomerulonephritis （AGN）, 20 Henoch-Schoenlein purpura nephritis （HSPN）, and 22 isolated hematuria （IHU）. A correlation analysis between renal pathological scores and FGFR4 expression was performed. Results 1 ） FGFR4 expression was weakly in renal vesicle and primitive tubules of S-shaped body, irrecognizable in urteric bud and podocytes of C-stage, and negative in mesenchyme and condensing mesenchyme. The immunostaining of FGFR4 was intense in distal tubules and collecting ducts, but was negative in mature glomeruli and proximal tubules. 2） FGFR4 was expressed in all pathological sections of various renal diseases. FGFR4 expression was intense in tubules but weak in glomeruli. It was principally expressed in distal tubules and partially in proximal tubules. The tubules with very strong expressions of FGFR4 presented abnormal structures including dilation and atrophy, especially in proximal tubules. 3 ） There were no significant differences in the FGFR4 expression in various parts of the kidney among various renal diseases. There were also no significant differences in the FGFR4 expression in renal tubules among the four different pathological types of renal diseases： focal segmental glomerularsclerosis （FSGS）, membranoproliferative glomertdonephritis （ MPGN）, mesangial proliferative glomerulonephritis（ MsPGN）, and minimal change disease （MCD）. The FGFR4 expression in podocytes in the MPGN group was noticeably higher than that of the other pathological type group （ P 〈 0.05 ）. 4 ） The FGFR4 expression in proximal tubules positively correlated with the pathological score of tubules （ r = 0.463682, P 〈 0.05 ） but negatively correlated with the pathological score of glomeruli （ r = - 0.0277, P 〈 0.05 ）. The FGFR4 expression in both distal tubules and podocytes negatively correlated with the pathological score of tubules or glomertdi （ P 〈 0.05 ）. Conclusions The development of fetal kidneys in the early period could not be regulated by FGF- FGFR4 signal which takes part in the development of renal tubules and collecting duct in the mature period. The FGFR4 expression is related with renal pathology in children with PNS, AGN, HSPN or IHU. A proper increase of FGFR4 expression is beneficial to the recovery of renal tissues but an over-expression relates to a severe renal damage.