| [Background/Aims] This thesis is made up of3parts. The first, we reviewed the general situation about the treatment of chronic renal failure (CRF) with uremic clearance (UC), a Chinese herbal compound preparation, which has the function of invigorating spleen and clearing dampness, clearing the hollow viscera and discharging the turbidity, and promoting blood circulation for removing blood stasis. The effects of UC on treating CRF in clinical pharmacodynamics mainly refer to improving renal function and the complications of CRF. The mechanisms of UC on treating CRF in pharmacology basically include depressing transforming growth factor (TGF)-β1over-expression, lessening podocyte injury, inhibiting tubular epithelial myofibroblast transdifferentiation, ameliorating microinflammation status, retarding oxidative stress, and alleviating insulin resistance. The second, we summarized the molecular mechanisms of matrix metalloproteinases (MMPs) regulation and extracellular matrix (ECM) degradation in the kidney and the interventional effects of Chinese herbal medicine (CHM). It is reported, the reduction of ECM degradation in the kidney is taken as the morphological features and pathological basis under renal damage in chronic kidney disease (CKD). ECM degradation is controlled by the catabolic enzyme systems, composed of MMPs and TIMPs(tissue inhibitors of metalloproteinases) in glomerulus and renal interstitium, in which MMPs play a key role. The expression and activity of MMPs are regulated by some classical pathways, such as the genic transcription, the activation of zymogen, and the specific inhibitor. Additionally, it is closely related with TGF-β1/Smads signaling pathway. The previous studies showed that, UC, as a representational prescription of CHM, and some extracts from CHM could intervene the pathway of ECM degradation through promoting the degradation of ECM components, affecting the expression of catabolic enzymes, regulating the genetic transcription of MMPs, and inhibiting the relative signaling transduction of MMPs. Finally, as a focal point in this thesis, we demonstrated that the mechanism of UC on regulating MMPs and related signaling pathway in model rats with renal failure. Renal failure model was established by adenine administration and unilateral ureteral obstruction (UUO). Compared with enalapril treatment in model rats, we firstly examined the protective effects of UC on renal function, then, clarified the regulative actions of UC on ECM degradation and MMPs/TIMPs, finally, demonstrated the potential mechanisms of UC on promoting ECM degradation through regulating TGF-β1/Smads signaling pathway.[Methods] Twenty-six Sprague-Dawley(SD)rats were randomly divided into4groups: the normal group, the model group, the UC group (5g/kg/day), and the enalapril group (0.02g/kg/day). The rats with renal failure, induced by adenine (from day1to14) and unilateral ureteral obstruction (UUO) on day15. All rats were killed on day21after the administration. The rats’24h urinary protein excretion (Upro), urinary N-acetyl-D-glucosaminidase (UNAG), blood biochemical parameters, and renal morphological changes were examined. In addition, the protein expressions of MMP-2, MMP-9, and TIMP-1, as well as TGF-β1phosphorylated-Smad2/3(p-Smad2/3), and Smad7, were analyzed respectively.[Results] After the intervention of UC, the general state of health, renal appearance, and blood biochemical parameters including serum creatinine(Scr), blood urea nitrogen(BUN), uric acid (UA), and albumin (Alb), as well as Upro, UNAG, and renal morphology change in model rats were improved in different degrees, respectively. Among them, the effect of UC on ameliorating Scr, BUN, UA, and Alb was similar to that of enalapril, whereas, the action of UC on attenuating collagen deposition did better than that of enalapril. In addition to these, in model rats, UC significantly up-regulated the protein expressions of MMP-2and MMP-9, and that, down-regulated the protein expression of TIMP-1in the kidney. In contrast with enalapril, UC appeared more the effectiveness on strengthening MMP-9and suppressing TIMP-1.On the other hand, UC down-regulated the protein expressions of TGF-β1and p-Smad2/3, and that, up-regulated the protein expression of Smad7in the kidney. The action of UC on suppressing TGF-β1and elevating Smad7did better than that of enalapril as well.[Conclusion] As for model rats with renal failure, UC had effects on ameliorating renal function; UC could improve ECM degradation through modulating the protein expressions of MMP-2, MMP-9, and TIMP-1; UC could promote ECM degradation by regulating bidirectionally the key signaling molecules including TGF-β1, p-Smad2/3, and Smad7in TGF-β1/Smads signaling pathway in the kidney. |
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