Effect of fibroblast-specific suicidal-gene against rapidly progressive glomerulonephritis

肾纤维化程度是各种进行性肾脏疾病功能预后的最佳预测指标。间质成纤维细胞和成纤维细胞样细胞（FbLCs）可能参与了纤维化过程。然而，此类fblc在肾脏中从未得到很好的表征。因此，在本研究中，我们使用免疫组织化学和表型和功能标记探针的原位杂交来表征它们。在抗肾小球基底膜（αGBM）肾病肾间质中，成纤维细胞特异性蛋白1 (FSP1)^+成纤维细胞产生结缔组织生长因子（CTGF）和I型胶原（COLI），而vimentin^+ FbLCs合成转化生长因子-β1。为了证明FSP1^+成纤维细胞是否在肾纤维化中起重要作用，我们在FSP1启动子（FSP1.dTK^+）的控制下，利用转基因小鼠来表达胸苷激酶（dTK） cDNA的缺失形式。由于转基因FSP1^+成纤维细胞TK蛋白双阳性，且这些增殖细胞在更昔洛韦（GCV）作用下发生凋亡，我们在它们体内产生αGBM肾炎，并用GCV治疗。在αGBM肾病肾中这些FSP1。在dTK^+小鼠中，GCV处理显著抑制了FSP1^+成纤维细胞数量的增加以及CTGF和COLI的产生，从而成功地抑制了肾纤维化的发生。FSP1^+被证明是肾脏纤维化的主要贡献者，FSP1基因引导的抗纤维化治疗似乎对各种进行性肾脏疾病有希望。

The extent of renal fibrosis is the best predictor for functional outcomes in a variety of progressive renal diseases. Interstitial fibroblasts and fibroblast-like cells (FbLCs) are presumably involved In the fibrotic process. However, such FbLCs have never been well-characterized in the kidney. Therefore, in this study, we characterized them using immunohistochemistry and in situ hybridization with phenotypic and functional marker probes. In the interstitium of anti-glomerular basement membrane (αGBM) nephritic kidneys, fibroblast-specific protein1 (FSP1)^+ fibroblasts were demonstrated to produce connective tissue growth factor (CTGF) and type I collagen (COLI) whereas vimentin^+ FbLCs synthesized transforming growth factor-β1. To prove whether FSP1^+ fibroblasts played an essential role in renal fibrogenesis, we employed mice transgenic for a deleted form of thymidine kinase (dTK) cDNA under the control of FSP1 promoter (FSP1.dTK^+). Since the transgenic FSP1^+ fibroblasts were dual-positive for TK protein, and these proliferating cells went apoptosis when gancyclovir (GCV) was administered, we generated αGBM nephritis in them and treated them with GCV. In the αGBM nephritic kidney of these FSP1.dTK^+ mice, GCV treatment significantly suppressed the increase in the number of FSP1^+ fibroblasts and the production of CTGF and COLI, resulting in the attenuation of renal fibrogenesis successfully. FSP1^+ were demonstrated to be a master contributor in the fibrosing kidneys, and the FSP1 gene-guided anti-fibrotic therapies seem promising for a variety of progressive renal diseases.