Rhee Harin, Han Miyeun, Kim Sang Soo, Kim Il Young, Lee Hye Won, Bae Sun Sik, Ha Hong Koo, Jung Eun Soon, Lee Min Young, Seong Eun Young, Lee Dong Won, Lee Soo Bong, Lovett David H, Song Sang Heon
Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.
Department of Internal Medicine, Pusan National University Hospital, Busan, Korea.
Kidney Res Clin Pract. 2018 Sep;37(3):222-229. doi: 10.23876/j.krcp.2018.37.3.222. Epub 2018 Sep 30.
This study was undertaken to explore the effects of aging on the kidneys in mouse models of diabetes and chronic kidney disease (CKD), and to compare the expression of two isoforms of matrix metalloproteinase-2 (MMP-2)-secretory full-length MMP-2 and intracellular N-terminal truncated MMP-2 (NTT-MMP-2)-in these models.
Two experimental ICR mouse models were used: a streptozotocin (STZ)-induced type 1 diabetes mellitus model and a 5/6 nephrectomized (5/6Nx) CKD model. The abundance of each isoform of MMP-2 was determined by quantitative polymerase chain reaction (qPCR), and functional analyses were conducted. Moreover, the protein levels of the two MMP-2 isoforms were determined semi-quantitatively by immunohistochemical staining, and their association with tissue damage was assessed.
Both isoforms of MMP-2 were upregulated in the kidney tissues of STZ-induced diabetic mice and 5/6Nx mice, irrespective of age. Characteristically, NTT-MMP-2 protein expression was elevated in old control mice, in line with the qPCR results. NTT-MMP-2 expression was limited to the renal cortex, and to the tubulointerstitial area rather than the glomerular area. In terms of tissue damage, tubulointerstitial fibrosis was more severe in old 5/6Nx mice than in their young counterparts, whereas glomerulosclerosis was comparable in old and young 5/6Nx mice.
The intracellular isoform of MMP-2 was induced by ageing, irrespective of the presence of diabetes or CKD, and its induction may be related to tubulointerstitial fibrosis in chronic kidney disease.
本研究旨在探讨衰老对糖尿病和慢性肾脏病（CKD）小鼠模型肾脏的影响，并比较基质金属蛋白酶-2（MMP-2）的两种同工型——分泌型全长MMP-2和细胞内N端截短型MMP-2（NTT-MMP-2）——在这些模型中的表达情况。
使用了两种实验性ICR小鼠模型：链脲佐菌素（STZ）诱导的1型糖尿病模型和5/6肾切除（5/6Nx）的CKD模型。通过定量聚合酶链反应（qPCR）测定MMP-2各同工型的丰度，并进行功能分析。此外，通过免疫组织化学染色半定量测定两种MMP-2同工型的蛋白水平，并评估它们与组织损伤的相关性。
在STZ诱导的糖尿病小鼠和5/6Nx小鼠的肾脏组织中，MMP-2的两种同工型均上调，与年龄无关。其特征是，NTT-MMP-2蛋白表达在老年对照小鼠中升高，与qPCR结果一致。NTT-MMP-2的表达仅限于肾皮质和肾小管间质区域，而非肾小球区域。在组织损伤方面，老年5/6Nx小鼠的肾小管间质纤维化比年轻小鼠更严重，而老年和年轻5/6Nx小鼠的肾小球硬化程度相当。
无论是否存在糖尿病或CKD，MMP-2的细胞内同工型均由衰老诱导，其诱导可能与慢性肾脏病中的肾小管间质纤维化有关。
