Effects and mechanisms of Shenkang injection promoting extracellular matrix degradation via regulating ERK1/2/MMPs signaling pathway in renal failure rats / 中国中药杂志

This study aimed to clarify preliminarily the effects and mechanisms of Shenkang injection (SKI) promoting extracellular matrix(ECM)degradation via regulating extracellular-signal regulated protein kinase(ERK)1/2/matrix metalloproteinases(MMPs)signaling pathway in renal failure rats. Twenty rats were randomly divided into 4 groups：the Sham group,the Model group,the SKI group and the Enalapril maleate(EM)group. The model rats with renal failure were induced by intragastric administration of adenine and unilateral ureteral obstruction(UUO). After modeling, the rats in SKI group and EM group were intervened by intraperitoneal injection of SKI or intragastric administration of the EM suspension,while the rats in Sham group and Model group were administrated with distilled water respectively for 3 weeks. The 24 h urinary protein excretion(Upro)and urinary N-acety1-β-D-glucosaminidase(UNAG)in all rats were tested after drug administration. All rats were sacrificed after drug administration for 3 weeks,blood and kidney were collected,renal morphological characteristics were observed. Furthermore,serum biochemical indices and the protein expressions of collagen type IV(CIV),MMP-2,MMP-9,tissue inhibitors of metalloproteinase(TIMP)-1,ERK1/2 and phosphorylated-ERK1/2(p-ERK1/2)in the kidney were evaluated respectively. The results indicated that,after the intervention of SKI,serum creatinine(Scr),blood urea nitrogen(BUN),uric acid(UA),albumin(Alb),Upro,UNAG and renal morphological change in model rats were improved at different levels,respectively. Moreover,these actions were similar to EM. In addition to these,SKI adjusted the protein expressions of MMP-2,MMP-9 and TIMP-1,and down-regulated the protein expressions of p-ERK1/2 in the kidney. Moreover,these actions were different from EM. In conclusion,SKI promotes ECM degradation and delays the progression of renal failure possibly through regulating ERK1/2 signaling pathway activation in the kidney and intervening MMPs/TIMP-1 expressions in vivo.

Effects and mechanisms of UCG ameliorating renal interstitial fibrosis by regulating TGF-β1/SnoN/Smads signaling pathway in renal failure rats / 中国中药杂志

This study was aimed to demonstrate preliminarily the effects and mechanisms of uremic clearance granule (UCG) ameliorating renal interstitial fibrosis (RIF) by regulating transforming growth factor (TGF)-β1/SnoN/Smads signaling pathway in vivo. Fifteen rats were randomly divided into 3 groups：the normal group,the model group and the UCG group. The rats with renal failure were induced by intragastric administration of adenine and unilateral ureteral obstruction (UUO). After modeling,the rats in the UCG group and in the other groups were intervened by intragastric administration of UCG and distilled water respectively during 3 weeks. The body weight and 24 h urinary protein excretion (Upro) in all rats were tested after drug administration. All rats were killed after drug administration for 3 weeks,blood and kidneys were collected and weighted,kidney appearance and renal morphological characteristics were observed. In addition,serum biochemical indices and the protein expressions of TGF-β1,SnoN,phosphorylated Smad2/3 (p-Smad2/3) and Smad7 in the kidney were evaluated respectively. The results indicated that,after the intervention of UCG,the general state of health,kidney appearance,serum creatinine (Scr),blood urea nitrogen (BUN),uric acid (UA),albumin (Alb),Upro and renal morphological change in model rats were improved in different degrees,respectively. Moreover,UCG down-regulated the protein expressions of TGF-β1 and p-Smad2/3,and up-regulated the protein expressions of SnoN and Smad7 in the kidney. In conclusion,UCG reduces extracellular matrix (ECM) synthesis and delays the progression of renal failure via possibly multi-targeting at regulating TGF-β1/SnoN/Smads signaling pathway in vivo.

Pathomechanisms of podocyte injury in diabetic nephropathy and interventional effects of Chinese herbal medicine / 中国中药杂志

Podocyte injury is closely related to proteinuria in the progress of diabetic nephropathy(DN). The pathological characters of podocyte injury mainly refer to the change of podocyte form and function, including foot process effacement, reduction of podocyte number and density, podocyte apoptosis, podocyte epithelial-mesenchymal transdifferentiation(EMT)and podocyte hypertrophy. These pathological damages are controlled by multiple signaling pathways in the kidney, such as mammalian target of rapamycin(mTOR)/autophagy pathway, transforming growth factor(TGF)-β1 pathway and Notch pathway. For podocyte injuries induced by high glucose or in murine models of DN, some Chinese herbal medicine(CHM)extracts, such as multiglycoside of Tripterygium wilfordii(GTW), triptolide(TP), astragaloside IV(AS-IV), astragalus polysaccharide(APS)and Panax notoginseng saponins(PNS), have the protective effects in vivo or in vitro. The preliminary studies in China showed that GTW improves podocyte injury in the DN model rats probably through regulating the activity of mTORC1 signaling pathway in the kidney. Therefore, it is the developmental direction for the further study to clarify the interventional effects of CHM based on podocyte injury-related signaling pathway in DN.

Regulative mechanisms of mammalian target of rapamycin signaling pathway in glomerular hypertrophy in diabetic nephropathy and interventional effects of Chinese herbal medicine / 中国中药杂志

Glomerular hypertrophy is the main pathological characteristic in the early stage of diabetic nephropathy (DN), and its regulatory mechanism is closely related to mammalian target of rapamycin (mTOR) signaling pathway activity. mTOR includes mTOR complex 1 (mTORC1) and mTOR complex 2(mTORC2), in which, the upstream pathway of mTORC1 is phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase(Akt)/adenosine monophosphate activated protein kinase(AMPK), and the representative signaling molecules in the downstream pathway of mTORC1 are 4E-binding proteins(4EBP) and phosphoprotein 70 S6Kinase(p70S6K). Some Chinese herbal extracts could improve cell proliferation via intervening the expressions of the key molecules in the upstream or downstream of PIK/Akt/mTOR signaling pathway in vivo. As for glomerular mesangial cells(MC) and podocyte, mTOR plays an important role in regulating glomerular inherent cells, including adjusting cell cycle, energy metabolism and matrix protein synthesis. Rapamycin, the inhibitor of mTOR, could suppress glomerular inherent cell hypertrophy, cell proliferation, glomerular basement membrane (GBM) thickening and mesangial matrix deposition in model rats with DN. Some Chinese herbal extracts could alleviate glomerular lesions by intervening mTOR signaling pathway activity in renal tissue of DN animal models or in renal inherent cells in vivo and in vitro.

Regulative mechanisms of oxidative stress in kidney in diabetic nephropathy and interventional effects of Chinese herbal medicine / 中国中药杂志

In the development of diabetic nephropathy (DN), reactive oxygen specie (ROS) over much in vivo leads to oxidative stress(OS)-related renal injuries, which are characterized by the structural and functional changes in glomerular and renal tubular cells in morphology. The regulative approaches of OS involve the several signaling pathways, in which, both p38 mitogen-activated protein kinase (MAPK) signaling pathway and adenosine monophosphate-activated protein kinase (AMPK) signaling pathway play the important roles as the target of anti-oxidants. The interventional actions of Chinese herbal compound prescriptions and the extracts of single Chinese herbal medicine (CHM) on OS in the kidney in DN include regulating the balance between ROS and antioxidants, reducing the production of AGEs, inhibiting the expression of growth factors and intervening the activity of signaling pathways.

Recognition of experimental animal model with kidney disease / 中国中药杂志

Animal models with kidney disease are generally divided into two types. One belongs to the models which imitate human kidney disease by the artificial operations, such as anti-glomerular basement membrane antibody nephritis, Heymann nephritis, anti-Thyl. 1 antibody nephritis, BSA nephritis and puromycin nephropathy. The other one pertains to the models which make themselves kidney disease, and appear the pathological characteristics naturally as like as human, such as HIGA mice with IgA nephropathy and NZB/WF1 and MRL/1pr mice with lupus nephritis. In addition,the transgenic animal models with kidney disease can also be established by the modern molecular biologic techniques including gene knockout and siRNA transfection. As for the studies related with kidney disease in pharmacodynamics and pharmacology of Chinese herbal medicine (CHM), it is important to understand deeply the features of each animal model with kidney disease, and select accurately the proper models according to the different experimental objectives, and then, build the special models provided with the combination of disease with syndrome in traditional Chinese medicine (TCM). Therefore,it is the developmental direction for the further study to establish animal models with kidney disease, which should possess the characteristics of syndrome in TCM.

Effects and mechanisms of multi-glycoside of Tripterygium wilfordii improving glomerular inflammatory injury by regulating p38MAPK signaling activation in diabetic nephropathy rats / 中国中药杂志

<p><b>OBJECTIVE</b>To explore the effects and mechanisms of multi-glycoside of Tripterygium wilfordii (GTW) on improving glomerular inflammatory lesion in rats with diabetic nephropathy (DN).</p><p><b>METHOD</b>DN model was induced by unilateral nephrectomy and intraperitoneal injection of STZ (35 mg x kg(-1)) twice. The rats were randomly divided into 3 groups, the sham-operated group (Sham group, n = 5), the vehicle-given group (Vehicle group, n = 5 ) and GTW-treated group (GTW group, n = 5). After the model was successfully established, the rats in GTW group were daily oral administrated with GTW suspension (50 mg x kg(-1) x d(-1)), meanwhile, the rats in Vehicle group were daily oral administrated with distilled water (2 mL) for 8 weeks. From the beginning of the administration, all rats were killed 8 weeks later. Blood and renal tissues were collected,and then UAlb, renal function, glomerular morphology characteristics and glomerular macrophages (ED1 + cells) infiltration, as well as the protein expressions of inflammatory cytokines including tumor necrosis factor(TNF)-α and interleukin(IL)-lβ, and the key molecules in p38MAPK signaling pathway including p38 mitogenactivated protein kinase (MAPK), phosphorylated p38 (p-p38MAPK) and transforming growth factor(TGF)-β1 were investigated respectively.</p><p><b>RESULT</b>GTW not only ameliorated the general state of health and body weight,but also attenuated UAlb, glomerulosclerosis, the infiltration of glomerular ED1 + cells and the protein expressions of TNF-α, IL-1β, p-p38MAPK and TGF-β1 in the kidney in DN model rats.</p><p><b>CONCLUSION</b>By means of DN model rats, we demonstrated that GTW has the protective effect on renal inflammatory damage in vivo via inhibiting inflammatory cells infiltration and inflammatory cytokines expression. Furthermore, GTW could improve renal inflammatory lesion through down-regulating the expressions of the key signaling molecules in p38MAPK pathway such as p-p38MAPK and TGF-β1 ,and inhibiting the activation of p38MAPK signaling in the kidney.</p>

Effects and mechanisms of huangkui capsule ameliorating renal fibrosis in diabetic nephropathy rats via inhibiting oxidative stress and p38MAPK signaling pathway activity in kidney / 中国中药杂志

<p><b>OBJECTIVE</b>To demonstrate the effects and mechanisms of Huangkui capsule (HKC) on renal fibrosis in rats with diabetic nephropathy (DN).</p><p><b>METHOD</b>Rats were randomly divided into 5 groups, the sham-operated group (Sham group, n = 5), the vehicle-given group (Vehicle group, n = 7), the low dose of HKC-treated group (L-HKC group, n = 7), the high dose of HKC-treated group (H-HKC group, n = 7) and the lipoic acid (LA)-treated group (LA group, n = 7). DN models were induced by intraperitoneal injection of streptozotocin (STZ,35 mg x kg(-1)) twice and unilateral nephrectomy. After models were successfully established, the rats in HKC and LA groups were daily administrated with HKC suspensions (0.75, 2 g x kg(-1)) or LA suspensions (60 mg x kg(-1)) respectively, and at the same time, the rats in Vehicle group were daily administrated with distilled water (2 mL) for 8 weeks. All rats were sacrificed at the end of week 8 to collect blood and renal tissues. UAlb, renal function, renal fibrotic morphologic characteristics, as well as oxidative stress (OS)-related markers, the protein expressions of the key signaling molecules in p38 mitogen-activated protein kinase (p38MAPK) signaling pathway, fibrogenic cytokines and inflammatory factors were examined respectively.</p><p><b>RESULT</b>HKC, similar to LA, improved the general state of health, body weight, UAlb, BUN, UA and Alb in DN model rats. Of note, renal fibrosis was ameliorated in HKC groups,especially in H-HKC group which was better than that in LA group. In addition, HKC not only improved the main indexes of OS in the kidney like LA, but also down-regulated the protein expressions of phosphorylated-p38MAPK (p-p38MAPK), transforming growth factor (TGF)-β1 and tumor necrosis factor(TNF)-α in the kidney, whereas, LA only decreased the protein expression of TNF-α in the kidney in DN model rats.</p><p><b>CONCLUSION</b>HKC, similar to LA, has the actions of anti-OS in vivo. Moreover, HKC could attenuate renal fibrosis by suppressing the activation of p38MAPK signaling pathway and the protein expressions of fibrogenic cytokines and inflammatory factors in the kidney in DN model rats, which is different from LA.</p>