Ureic clearance granule, alleviates renal dysfunction and tubulointerstitial fibrosis by promoting extracellular matrix degradation in renal failure rats, compared with enalapril.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal compound prescription has a unique therapeutic action on chronic kidney disease (CKD) in China. In clinics, Uremic Clearance Granules (UCG), a compounded Chinese patent medicine, has been frequently used to treat chronic renal failure (CRF) patients for nearly 30 years, however, the deep therapeutic mechanisms involved in vivo remain a challenge. This study aims to demonstrate the effects and mechanisms of UCG on renal dysfunction and tubulointerstitial fibrosis by regulating extracellular matrix (ECM) degradation and transforming growth factor (TGF)-beta1/Smad signaling activity in vivo, compared with enalapril. MATERIALS AND METHODS: Twenty-six rats were randomly divided into 4 groups, a sham-operated group (Sham group), a vehicle-intervened group (Vehicle group), a UCG-treated group (UCG group) (5g/kg/day) and an enalapril-treated group (Enalapril group) (20mg/kg/day). The rats with renal failure were induced by adenine (150 mg/kg/day) and unilateral ureteral obstruction (UUO), and killed on day 35 after the administration. Proteinuria, urinary N-acetyl-beta-D-glucosaminidase (UNAG), blood biochemical parameters, renal morphological changes, collagen type IV (CIV), matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase (TIMP)-1, as well as the key molecular protein expressions in TGF-beta1/Smad signaling pathway were observed, respectively. RESULTS: Adenine administration and UUO induced severe renal damages, as indicated by renal dysfunction, proteinuria and the marked histopathological injuries in the tubules and interstitium, which were associated with MMP-2/TIMP-1 imbalance and TGF-beta1/Smad signaling activity, as shown by up-regulation of the protein expressions of TGF-beta1, TGF-beta receptor type I (RI), TGF-beta receptor type II (RII), Smad2/3, phosphorylated-Smad2/3 (p-Smad2/3) and Smad4, as well as down-regulation of the protein expression of Smad7 in the kidney. UCG treatment, however, significantly not only attenuated renal dysfunction and tubulointerstitial fibrosis, but also improved the protein expressions of MMP-2, TIMP-1, TGF-beta1, TGF-beta RI, p-Smad2/3, Smad4 and Smad7 in the kidney. Besides, the effects of UCG were stronger than those of enalapril partly. CONCLUSION: UCG similar to enalapril, is renoprotective via ameliorating renal dysfunction and tubulointerstitial fibrosis in the renal failure model. The potential mechanisms by which UCG exerts its therapeutical effects in vivo are through promoting ECM degradation and regulating MMP-2/TIMP-1 balance or signaling molecular activity in TGF-beta1/Smad pathway in the kidney. These findings suggest that UCG treatment is undoubtedly useful in preventing the progression of CRF.

[Molecular mechanisms of renal extracellular matrix degradation and interventional effects of Chinese herbal medicine].

The reduction of extracellular matrix (ECM) degradation in kidney is taken as the morphological features and pathological base in renal injury in chronic kidney disease (CKD). ECM degradation is controlled by the catabolic enzyme systems in glomerulus and renal interstitium, in which matrix metalloproteinases (MMPs) play a key role. The expression and activity of MMPs are regulated by the classical pathway, such as the genic transcription, the activation of zymogen, and the specific inhibitor. The previous studies showed that, Uremic Clearance granule, as a representation, and other prescriptions of Chinese herbal medicine, as well as some extracts from Chinese herbal medicine 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.

[Overview research of uremic ulearance granule treating chronic renal failure].

The effective bioactivity compositions of uremic clearance granul (UCG) include isoflavonoids, emodin, astragaloside, paeoniflorin, salvianolic acid A, and so on. The effects of UCG treating chronic renal failure (CRF) in clinical pharmacodynamics mainly refer to improve renal function and the complications of CRF. The mechanisms involved in vivo basically include depressing transforming growth factor (TGF)-beta1 over-expression, lessening podocyte injury,inhibiting tubular epithelial myofibroblast transdifferentiation, ameliorating microinflammation status, retarding oxidative stress, and alleviating insulin resistance.

[Effects of huangkui capsule on renal inflammatory injury by intervening p38MAPK signaling pathway in rats with adriamycin-induced nephropathy].

OBJECTIVE: To explore the potential mechanisms of huangkui capsule (HKC), an extract from Abelmoschus manihot (AM), for ameliorating renal inflammatory injury by regulating p38 mitogen-activated protein kinase (MAPK) signaling pathway in rats with adriamycin-induced nephropathy (ADRN). METHOD: Nineteen Sprague-Dawley (SD) rats were randomly divided into three groups, the sham-operation group, the untreated model group,and the HKC-treated group. Rats in the untreated model group and the HKC-treated group were made into ADRN model by right nephrectomy and twice intravenous injections of adriamycin( ADR, 0.4 mL and 0.2 mL respectively within 4 weeks). After the model successfully established, rats in the HKC-treated group were orally given HKC (2 mg x kg(-1) per day), while rats in the untreated model group and the sham-operation group were intervened with distilled water respectively. The intervention for all rats was 4 weeks. Rats' body weight were weighted and 24 h urinary protein excretion (Upro) was detected at the end of the 1st, 2nd, 3rd, and 4th week after the intervention of HKC or distilled water. All rats were sacrificed at the end of the 8th week after nephrectomy, and then, to withdraw blood and kidney to examine the blood biochemical parameters, the glomerular morphological changes, alpha-smooth muscle actin (alpha-SMA) and collagen type I expressions,and the glomerular macrophages infiltration. Besides, the protein expression of transforming growth factor (TGF)-beta1, p38MAPK, as well as phosphorylated p38MAPK (p-p38MAPK) in renal tissues were detected by Western blotting. RESULT: As compared with rats in the untreated model group, in the HKC-treated group,the HKC treatment significantly improved Upro, serum albumin, mesangial cell proliferation, extracellular matrix (ECM) and collagen deposition,and decreased the expression of alpha-SMA and collagen type I and the infiltration of ED1+ and ED3+ cells in glomeruli. In addition, it significantly down-regulated the protein expression of TGF-beta1 and p-p38MAPK in renal tissues. CONCLUSION: HKC had the effects on ameliorating renal inflammatory injury in vivo. It could reduce the expression of TGF-beta1 and improve the infiltration and activation of inflammatory cells in glomeruli by way of intervening p38MAPK signaling pathway in kidney through down-regulating the protein expression of p-p38MAPK, as the key signal molecule.

Contrasting dose-effects of multi-glycoside of Tripterygium wilfordii HOOK. f. on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis.

Multi-glycoside, one of the extracted compounds from Tripterygium wilfordii HOOK. f. (GTW), has been shown to be clinically effective in suppressing glomerular inflammation in chronic kidney disease. However, its clinical application is often limited by its cytotoxic actions on the liver. This study was performed to contrast the dose-effects of GTW on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis (GN). Rats with acute or chronic anti-Thy1.1 GN were either left untreated (the Vehicle group) or treated with a high or low dose of GTW and sacrificed on day 7 or day 45. GTW was administrated 3 days before or at the same time as the antibody injection and lasted until sacrifice. GTW at high dose ameliorated glomerular macrophage accumulation, mesangial proliferation, proteinuria, and interleukin-2 expression in the acute anti-Thy1.1 GN model, but caused structural and functional lesions in the liver. In contrast, GTW at low dose improved activated macrophage and T lymphocyte infiltration, mesangial injury, proteinuria, and interleukin-2 and interferon-γ expressions without hepatic toxicity in the chronic model of GN induced by anti-Thy1.1 antibody. In conclusion, GTW at low dose not only effectively inhibits glomerular inflammation but also avoids severe injuries to the liver.