Analysis of glomerulosclerotic mechanism by monoclonal antibody-induced progressive renal lesion model in rats

单侧肾切除大鼠静脉注射抗Thy-1.1单抗(mAb1-22-3)500ug，造成可逆性硬化性肾损害。此模型的特点是持续明显的蛋白尿，并伴有肾小球和肾小管间质的典型硬化性病变。黏附分子抑制剂、补体抑制剂、抗纤维化药物、血管紧张素转换酶抑制剂和中药可抑制这些损伤。我们比较了各种参数可逆模型和可逆模型的动力学，两者都是由静脉注射单抗1-22-3诱导的。在不可逆模型中，TRPM3阳性的活化巨噬细胞和α-平滑肌动蛋白阳性细胞甚至在相对早期就已渗透到间质，这表明这些肾小管间质在导致不可逆转的硬化性病变中发挥了重要作用。血管紧张素受体拮抗剂通过在mRNA和蛋白水平抑制转化生长因子-β和I型、III型胶原的表达来阻止进展为终末期肾功能衰竭，表明这些因素在肾脏损害不可逆转的进展中也起着重要作用。

I rreversible sclerotic renal lesions were induced in rats by an intravenous injection of 500 ug of anti-Thy-1.1 monoclonal antibody (mAb) 1-22-3to unilaterally nephrectomized rats. This modelis characterized by the sustained marked proteinuria with typical sclerotic lesions in glomeruli as well as in tubulointerstitium. These lesions were inhibited by adhesive molecules suppressants, complement inhibitors, anti-fibrotic agents, ACE inhibitors and Chinese traditional medicines. We have compared the kinetics of various parametersofirreversible to those in reversiblemodels, both of which were induced by an intravenous injection of mAb 1-22-3. In irreversible models TRPM3-positive activated macrophage and alpha -smoothe muscle actin-positive cells were demonstrated to infiltrate to interstitium, even in relatively early phase, suggesting the important roles playd by these tubulointerstitiallesionsin leading to irreversiblescleroticlesions. Angiotensin receptorantagonist prevented progression to endo-stage renal failure by suppressing the expression of TGF-beta and type I,III collagens at mRNA and protein levels, indicating that these factors are also important for irreversible progression of renal lesions.