Yoshimura Hiromitsu, Ito Masayoshi, Kuwahara Yusuke, Ishii Aiko, Tsuritani Katsuki, Nakamura Atsushi, Hirasawa Yasushi, Nagamatsu Tadashi
Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, 331-9530, Japan.
Life Sci. 2008 Apr 9;82(15-16):899-908. doi: 10.1016/j.lfs.2008.02.006. Epub 2008 Feb 23.
This study discusses the critical role of the metalloproteinase meprinbeta in the progression of glomerulonephritis. Using a microarray technique, the gene expression profiles in glomeruli isolated from high serum IgA (HIGA) mice with a purity of 97% or greater were examined. HIGA mice are a valid model of human IgA nephropathy (IgAN), with the typical pathological features of this condition, including a consistently high serum IgA level as well as dominant mesangial IgA deposition and mesangial enlargement. Among the many upregulated/downregulated genes after the development of IgAN, the downregulation of meprinbeta was intriguing. The expression level of the meprinbeta gene at 40 weeks of age was 52% of that observed at 8 weeks of age (prior to the development of IgAN), although in the control BALB/c mice, a 2.19-fold elevation was seen. These results were also confirmed by semi-quantitative RT-PCR and immunostaining analyses. As meprinbeta is a subunit of metalloproteinase meprins (meprin A, meprin B) and meprins are capable of proteolytically degrading extracellular matrix (ECM) components and proteolytically processing bioactive peptides, the downregulation of meprinbeta may contribute to the progression of glomerulonephritis and the eventual glomerular scarring. This working hypothesis was examined using an in vivo meprinbeta inhibition study. The inhibition of meprins by actinonin exacerbated some parameters of renal injury in mice afflicted with anti-glomerular basement membrane (anti-GBM) antibody-associated nephritis. These in vitro and in vivo results suggest that meprinbeta may play a protective role against the progression of renal injury through the degradation of ECM and bioactive peptides.
本研究探讨了金属蛋白酶meprinβ在肾小球肾炎进展中的关键作用。采用微阵列技术，检测了从血清IgA高（HIGA）小鼠分离的纯度为97%或更高的肾小球中的基因表达谱。HIGA小鼠是人类IgA肾病（IgAN）的有效模型，具有该疾病的典型病理特征，包括持续高血清IgA水平以及主要的系膜IgA沉积和系膜增大。在IgAN发生后许多上调/下调的基因中，meprinβ的下调令人感兴趣。40周龄时meprinβ基因的表达水平是8周龄（IgAN发生前）观察到的表达水平的52%，尽管在对照BALB/c小鼠中，观察到有2.19倍的升高。这些结果也通过半定量RT-PCR和免疫染色分析得到了证实。由于meprinβ是金属蛋白酶meprin（meprin A、meprin B）的一个亚基，且meprin能够蛋白水解降解细胞外基质（ECM）成分并对生物活性肽进行蛋白水解加工，meprinβ的下调可能有助于肾小球肾炎的进展及最终的肾小球瘢痕形成。使用体内meprinβ抑制研究对这一工作假设进行了检验。放线菌素对meprin的抑制加剧了患有抗肾小球基底膜（anti-GBM）抗体相关肾炎的小鼠的一些肾损伤参数。这些体外和体内结果表明，meprinβ可能通过降解ECM和生物活性肽对肾损伤的进展发挥保护作用。
