| Summary: | 博士 === 中山醫學大學 === 醫學研究所 === 102 === Introduction
Abnormal balance turnover of extracellular matrix and overproduction of reactive oxygen species （ROS）have roles in renal fibrosis. Matrix metalloproteinases （MMPs）is associated with many glomerular diseases. Reactive oxygen species have been proposed to be associated with multiple diseases and also a risk factor at the development of post-transplant complications, including renal dysfunction, graft failure, patient death, and diabetes mellitus. Glutathione S-transferases（GST）is reported to be associated with effects against oxidative stress and was reported to be associated with the occurrence of diabetes mellitus. 8-hydroxy-2’ deoxyguanosine （8-OHdG）, a metabolite of oxidative damage to leukocyte DNA, has been identified as a marker of oxidative stress in patients with chronic renal failure. Because the histological association of MMPs and 8-OHdG and human renal fibrosis is unclear, we conducted this study to evaluate their relationship
Materials and Methods
This is a retrospective study. Institutional Review Board approval was obtained for the review of patients’ medical records, data analysis and pathological specimens staining with waiver of informed consents. Specimens of seventy-four patients were examined by immunohistochemical stain of MMP-9 and 8-OHdG in nephrectomized kidneys, and the association between renal expression of MMP-9 and 8-OHdG and renal fibrosis were determined. MMP-9 and 8-OHdG expression in individual renal components and fibrosis were graded as high or low based on MMP-9 and 8-OHdG staining and fibrotic scores.
Results
After evaluation the relationship between renal fibrosis and MMP-9, we found that patients with high interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), and were more likely to have chronic kidney disease (CKD) and urothelial cell carcinoma. Univariate analysis showed that IFS and GFS were negatively associated with normal and atrophic tubular cytoplasmic MMP-9 expression and IFS was positively correlated with atrophic tubular nuclear MMP-9 expression. Multivariate stepwise regression indicated that MMP-9 expression in atrophic tubular nuclei（r = 0.4；p = 0.002）was an independent predictor of IFS, and that MMP-9 expression in normal tubular cytoplasm（r = -0.465；p < 0.001）was an independent predictor of GFS.
After evaluation the relationship between renal fibrosis and MMP-9, we found that Patients with higher IFS and GFS had significantly higher serum creatinine, lower eGFR, increased percentage of CKD and urothelial cell carcinoma. The renal tissues with higher IFS had lower expressions of 8-OHdG in normal tubular cytoplasm (NTc) (35.7% vs. 64.3%, p = 0.011) and normal tubular nuclei (NTn) (28.6% vs. 71.4%, p = 0.023). Univariate analysis showed that IFS and GFS correlated with the NTc 8-OHdG expression and IFS negatively correlated with NTn 8-OHdG expression. Multivariate stepwise regression revealed that serum creatinine (r = 0.351 for IFS, p = 0.021; r = 0.563 for GFS, p < 0.001) and intensity of 8-OHdG expression in NTc (r = 0.397 for IFS, p = 0.01; r = 0.278 for GFS, p = 0.043) were the independent factors predicting IFS or GFS.
Conclusion
Our results indicate that severity of renal fibrosis is associated with a decline of MMP-9 expression in the cytoplasm of normal tubular cells, increased expression of MMP-9 in the nuclei of tubular atrophic renal tubules, and increased expression of 8-OHdG intensity in normal tubular cytoplasm.
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