| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 103 === End-stage renal disease (ESRD) threatens not only affected individuals but also burdens the financial health of nations. In Taiwan, 40% of ESRD patients are resulted from diabetic kidney disease (DKD). DKD is characterized by excessive deposition of extracellular matrix proteins and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to DKD. We used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in DKD. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.
To link the crosstalk between glomerular disease and tubular injury, we investigate the association between proteinuria and acute kidney injury (AKI) in patients with preserved glomerular filtration rate (GFR). 1246 cardiac surgery patients were included in study with mean estimated GFR 80 ± 13 ml/min/1.73m2. Proteinuria was present in 290 patients (23.4 %). 434 patients (34.8 %) developed post-operative AKI. The crude risk of AKI was greater in patients with higher grade of proteinuria. In subgroup analysis for gender, diabetes and surgical type, pre-operative proteinuria remains a strong risk factor of AKI following cardiac surgery. We demonstrated that urine protein strongly and independently predict the post-operative AKI risk among subjects with preserved estimated GFR.
These findings from serial studies may hopefully elucidate the role of MMP in podocyte injury, proteinuria and subsequently tubular disease. It raise a rationale to possible therapeutic MMPs manipulation in kidney disease in the future.
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