TISSUE POLARITY GENE FRIZZLED IS EXPRESSED IN THE INTERSTITIAL MYOFIBROBLASTS IN A RENAL FIBROSIS.

间质纤维化是许多慢性肾脏疾病的最终事件，而肌成纤维细胞的存在在这一过程中是至关重要的。肌成纤维细胞(α-平滑肌肌动蛋白阳性，α-SMA+)的存在在很大程度上局限于正常肾脏的血管平滑肌细胞，但在纤维化发展过程中延伸至肾小管间质和肾小球周围间隙。控制肌成纤维细胞定位的机制尚不清楚，但可能涉及极性信号的传递。这种控制的可能候选基因是果蝇极性基因Frizzed的大鼠同源基因。在果蝇中，卷曲的基因控制着翅膀毛发的生长。在哺乳动物中，已鉴定出两个高度同源的基因(fr1和fz2)。本研究的目的是定位和定量fz2在单侧输尿管梗阻大鼠肾脏中的表达，以探讨其在间质纤维化中肌成纤维细胞定位的空间调控中的作用。在输尿管梗阻后1、2、3、5周及正常肾连续切片上进行α-SMA免疫组织化学染色和FZ2基因原位杂交。正常肾组织中未见α+肌成纤维细胞，1周后间质中可见FZ2+肌成纤维细胞；间质中FZ2+肌成纤维细胞数量在3周达高峰，5周时间质纤维化扩张，FZ2+肌成纤维细胞数量下降。总之，在单侧输尿管梗阻模型中，肌成纤维细胞表达果蝇组织极性基因fz2的同源基因，并且fz2的表达参与了单侧输尿管梗阻模型间质纤维化早期的空间调控。

Interstitial fibrosis is the final event of many chronic renal diseases, and the presence of myofibroblast is critical in the process. Presence of myofibroblasts (a-smooth muscle actin positive, αSMA+) is confined to a large extent to the vascular smooth muscle cells of normal kidneys but extends to the tubulointerstitium and periglomerular space in the development of fibrosis. The mechanisms that control the myofibroblast localization are unknown, but are likely to involve the transmission of polarity signals. Possible candidate genes for this control are the rat homologues of the Drosophila polarity gene frizzled. In Drosophila, the frizzled gene controls the polarity of the wing hair growth. In mammalians, two highly homologous genes (fri and fz2) have been identified. The aims of the present study were to localize and to quantify the expression of fz2 in rat kidney in the course of unilateral ureteral obstruction, in order to study their putative role in the spatial control of myofibroblast localization in interstitial fibrosis. Immunohistochemistry for αSMA and in situ hybridization for the frizzled gene fz2 are performed on serial sections at 1, 2, 3 and 5 weeks after ureteral obstruction as well as normal kidney. Gradual increase in the number of αSMA+ cells in interstitium was demonstrated from week 1 to week 5.There was no fz2+ myofibroblast in normal kidney, however it appeared in the interstitium from week 1. The peak of the number of fz2+ myofibroblast in the interstitium was shown at week 3 and it decreased at week 5 when the expansion of interstitial fibrosis was demonstrated. In conclusion, myofibroblasts express a homologue of Drosophila tissue polarity gene frizzled (fz2) and fz2 expression in myofibroblasts is involved in the spatial control of the early phase of interstitial fibrosis in a unilateral ureteral obstruction model.