OBJECTIVETo evaluate the renal protective effect of Tangshenkang Granule () in a rat model of diabetic nephropathy (DN).

METHODSForty male Sprague-Dawley rats were randomly divided into control, DN, Tangshenkang and benazepril groups. DN model was established in the rats of DN, Tangshenkang and benazepril groups. Tangshenkang Granule solution and benazepril hydrochloride solution were intragastrically administered daily to the rats in the Tangshenkang and benazepril groups for 8 weeks, respectively. Urinary albumin and creatinine were detected. The albumin/creatinine (ACR) was calculated in addition to 24 h urinary protein (24-h UPr), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and creatinine clearance rate (Ccr). Right kidneys were harvested for pathological observation using periodic acid-silver methenamine-Masson staining. The average glomerular diameter (DG), average glomerular (AG) and mesangial areas (AM) were measured. The thickness of glomerular basement membrane (TGBM) was detected using transmission electron microscope.

RESULTSCompared with rats in the control group, rats in the DN group showed significantly decreased body weight, increased hypertrophy index, 24-h urinary volume, 24-h UPr, ACR, Scr, BUN, Ccr, blood lipids as well as renal pathological indices including DG, AG, AM, AM/AG and TGBM (P <0.05). Compared with the DN group, the weights of rats in the Tangshenkang and benazepril groups were significantly increased, and the renal hypertrophy indices were significantly decreased (P <0.05). The 24-h urinary volumes, ACR, 24-h UPr, Scr, BUN, Ccr, LDL, DG, AG, AM and TGBM were obviously decreased (P <0.05). Compared with the benazepril group, the Tangshenkang group showed significantly decreased levels of ACR, 24-h UPr, AG and AM (P <0.05).

CONCLUSIONSTangshenkang Granule decreased the urinary protein, attenuated the high glomerular filtration rate and improved lipid metabolism in DN rats, and prevented further injury induced by diabetic nephropathy.

Albuminuria ; complications ; Animals ; Basement Membrane ; drug effects ; metabolism ; Blood Urea Nitrogen ; Body Weight ; drug effects ; Creatinine ; blood ; urine ; Diabetic Nephropathies ; blood ; drug therapy ; physiopathology ; urine ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hypertrophy ; Kidney Function Tests ; Kidney Glomerulus ; drug effects ; pathology ; physiopathology ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Male ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effects of rapamycin (RAP) on pulmonary hypertension (PH) in rats, and to provide new insights into medication selection for the clinical treatment of PH.

METHODSFifty male Sprague-Dawley rats were randomly divided into blank control, PH model, solvent control, RAP 1, and RAP 2 groups. A rat model of PH was induced by left pneumonectomy (PE) and monocrotaline (MCT). At 5 days after PH model establishment, the solvent control group and the RAP 1 group received an intramuscular injection of solvent and RAP, respectively. At 35 days after PH model establishment, the RAP 2 group received an intramuscular injection of RAP. The mean pulmonary artery pressure (mPAP) and the right ventricle/left ventricle plus septum weight ratio (RV/LV+S) were measured in each group. Histopathological changes in the right lung were evaluated by hematoxylin-eosin (HE) staining. The relative expression of alpha-smooth muscle actin (α-SMA) and smooth muscle protein 22-alpha (SM22α) in each group was determined using real-time PCR.

RESULTSAt 35 days after surgery, the PH model and the solvent control groups had significantly higher mPAP and RV/LV+S than the blank control group, while the RAP 1 and the RAP 2 groups had significantly lower mPAP than the solvent control group (P<0.05). The RV/LV+S in the RAP 1 group was significantly lower than that in the solvent control group (P<0.05); however, there was no significant difference in RV/LV+S between the RAP 2 and the solvent control groups (P>0.05). HE staining in the right lung showed the substantially thickened pulmonary artery wall and narrowed arterial lumen in the PH model and the solvent control groups compared with the blank control group. Different degrees of reversal of the pulmonary artery wall thickening were observed after RAP administration. The results of real-time PCR revealed that the relative expression of α-SMA and SM22α in the PH model and the solvent control groups was significantly lower than in the blank control group, while the relative expression of α-SMA and SM22α in the RAP 1 and the RAP 2 groups was significantly higher than in the solvent control group (P<0.05).

CONCLUSIONSRAP can reverse the increase in pulmonary artery pressure and the right ventricular hypertrophy probably by regulation of the phenotypic conversion of vascular smooth muscle cells.

Actins ; genetics ; Animals ; Hemodynamics ; Hypertension, Pulmonary ; drug therapy ; physiopathology ; Hypertrophy, Right Ventricular ; etiology ; Male ; Microfilament Proteins ; genetics ; Muscle Proteins ; genetics ; Pulmonary Artery ; pathology ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Sirolimus ; therapeutic use

Pulmonary arterial hypertension (PAH) causes right ventricular failure due to a gradual increase in pulmonary vascular resistance. The purposes of this study were to confirm the engraftment of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) placed in the correct place in the lung and research on changes of hemodynamics, pulmonary pathology, immunomodulation and several gene expressions in monocrotaline (MCT)-induced PAH rat models after hUCB-MSCs transfusion. The rats were grouped as follows: the control (C) group; the M group (MCT 60 mg/kg); the U group (hUCB-MSCs transfusion). They received transfusions via the external jugular vein a week after MCT injection. The mean right ventricular pressure (RVP) was significantly reduced in the U group after the 2 week. The indicators of RV hypertrophy were significantly reduced in the U group at week 4. Reduced medial wall thickness in the pulmonary arteriole was noted in the U group at week 4. Reduced number of intra-acinar muscular pulmonary arteries was observed in the U group after 2 week. Protein expressions such as endothelin (ET)-1, endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 significantly decreased at week 4. The decreased levels of ERA, eNOS and MMP-2 immunoreactivity were noted by immnohistochemical staining. After hUCB-MSCs were administered, there were the improvement of RVH and mean RVP. Reductions in several protein expressions and immunomodulation were also detected. It is suggested that hUCB-MSCs may be a promising therapeutic option for PAH.
Animals ; Cytokines/metabolism ; Disease Models, Animal ; Endothelin-1/metabolism ; Fetal Blood/*cytology ; Gene Expression Regulation/drug effects ; Hemodynamics ; Humans ; Hypertension, Pulmonary/chemically induced/*therapy ; Hypertrophy, Right Ventricular/physiopathology ; Immunohistochemistry ; Lung/metabolism/pathology ; Male ; Matrix Metalloproteinase 2/metabolism ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells/*cytology/metabolism ; Monocrotaline/toxicity ; Nitric Oxide Synthase Type III/metabolism ; Pulmonary Artery/pathology ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A/metabolism

OBJECTIVETo investigate whether total triterpene acids (TTAs), isolated from Cornus Fructus, attenuates renal function by reducing oxidative stress and down-regulating the expression of transforming growth factor β1 (TGF-β1).

METHODSDiabetes was induced by an injection of streptozotocin (40 mg/kg intravenously). Thirty rats were randomly divided into three groups: control group, diabetic model group and TTAs treatment group (50 mg/kg, intragastrically) administrated for 8 weeks from 5th to 12th week. All rats were anaesthetized and then were killed to remove kidneys. The renal function and redox enzyme system parameters were tested. Glomerular morphology was observed by a light microscopy. Immunohistochemistry and Western blot assays were employed to determine the protein levels of TGF-β1.

RESULTSTTAs attenuated the levels of urinary protein, serum creatinine and blood urea nitrogen, although it did not significantly reduce the level of glucose. In addition, TTAs decreased the malondialdehyde while increased superoxide dismutase, catalase and glutathione peroxide activities in diabetic rats. The renal pathological changes in TTAs treatment group were ameliorated. Furthermore, TTAs also ameliorated the expression of TGF-β1.

CONCLUSIONTTAs improved renal function via reducing oxidative stress and down-regulation the expression of TGF-β1 in diabetic rats.

Animals ; Blood Glucose ; metabolism ; Blood Urea Nitrogen ; Blotting, Western ; Body Weight ; drug effects ; Catalase ; metabolism ; Cornus ; chemistry ; Creatinine ; metabolism ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; pathology ; physiopathology ; Disease Progression ; Glutathione Peroxidase ; metabolism ; Hypertrophy ; Kidney ; drug effects ; pathology ; physiopathology ; Kidney Function Tests ; Male ; Malondialdehyde ; metabolism ; Rats, Sprague-Dawley ; Streptozocin ; Superoxide Dismutase ; metabolism ; Transforming Growth Factor beta1 ; metabolism ; Triterpenes ; isolation & purification ; pharmacology ; therapeutic use

OBJECTIVETo explore the effects and underlying mechanisms of Panax notoginoside (PNS) on the nephropathy in rats with type 1 diabetes.

METHODSA murine model of diabetic nephropathy was set up by an intravenous injection of streptozotocin (STZ). Wistar rats were randomly divided into 5 groups: the control group, the diabetic group (DM), the group treated with low-dosage PNS (PNS-L), the group treated with high-dosage PNS (PNS-H) and the group treated with catopril. Rats in the PNS-L and PNS-H groups were given different dosages of PNS while rats in the catopril group were given catopril through gastrogavage every day for the next four consecutive weeks. Serum creatinine (Cr) levels, endogenous creatinine clearance rate (CCr), and 24-h urinary microalbumin (UAlb) were examined and calculated. Meanwhile, immunohistochemistry was applied to determine the expression of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 (BMP-7) in the kidney tissue.

RESULTSThe levels of Cr, Ccr, and UAlb were all elevated significantly in the DM group (P<0.01). The expression of VEGF protein was increased but BMP-7 protein was decreased in the kidney tissue (P<0.01). However, the above items decreased in the PNS-L, PNS-H and catopril groups compared with the DM group (P<0.05, P<0.01). In the PNS-L, PNS-H and catopril groups, the expression of VEGF protein was decreased but BMP-7 protein was increased in the kidney tissue (P<0.05, P<0.01).

CONCLUSIONPNS shows protective effects on the kidney in type 1 diabetic rats at the early stage. The protective mechanism might be closely related to its role of inhibiting the expression of VEGF protein and enhancing the expression of BMP-7 protein in the kidney.

Animals ; Body Weight ; drug effects ; Bone Morphogenetic Protein 7 ; metabolism ; Diabetes Mellitus, Type 1 ; complications ; drug therapy ; pathology ; physiopathology ; Diabetic Nephropathies ; complications ; drug therapy ; pathology ; physiopathology ; Hypertrophy ; Immunohistochemistry ; Kidney ; drug effects ; metabolism ; pathology ; Kidney Function Tests ; Male ; Panax ; chemistry ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Proteinuria ; complications ; drug therapy ; pathology ; physiopathology ; Rats ; Rats, Wistar ; Vascular Endothelial Growth Factor A ; metabolism

The myocardial protective effects of endothelin antagonist in ischemic cardiomyopathy (ICMP), doxorubicin-induced cardiomyopathy (DOX) and pressure-overload hypertrophy by transverse aortic constriction (TAC) models have been predicted to be different. The objective of this experiment, therefore, is to evaluate the myocardial protective effect of tezosentan, an endothelin receptor antagonist, in various experimental heart failure models. Sprague-Dawley rats (6-8 weeks old, 200-300 g) were randomized to three experimental groups (n=30 each): ICMP; DOX; and TAC group. Each of these groups was randomly assigned further to the following subgroups (n=10 each): sham-operated ischemia-reperfusion subgroup (SHAM); tezosentan treated ischemia-reperfusion subgroup (Tezo); and tezosentan non-treated ischemia-reperfusion subgroup (N-Tezo). Total circulatory arrest was induced for 1 hr, followed by 2 hr of reperfusion. The left ventricular developed pressure, peak positive and negative first derivatives, and coronary blood flow were significantly different (P<0.05) among the SHAM, Tezo, and N-Tezo subgroups of the ICMP group at 30 min of reperfusion, but there were no statistically significant differences among the subgroups of the DOX and TAC groups. In conclusion, tezosentan, an endothelin receptor antagonist, showed myocardial protection effects only on the ischemic cardiomyopathy rat model, but not in the non-ischemic heart failure rat models.
Animals ; Cardiomyopathies/chemically induced/drug therapy/physiopathology ; Coronary Vessels/physiology ; Disease Models, Animal ; Doxorubicin/toxicity ; Heart Failure/*drug therapy/physiopathology ; Hypertrophy/drug therapy/physiopathology ; Male ; Pressure ; Pyridines/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, Endothelin/*antagonists & inhibitors/metabolism ; Reperfusion Injury/*drug therapy/physiopathology/surgery ; Tetrazoles/*therapeutic use ; Vasodilator Agents/*therapeutic use ; Ventricular Function, Left/physiology

OBJECTIVETo examine the change of puerarin on the expression of apelin and its receptor of the two-kidney, one-clip (2K1C) rats.

METHODTirty male Sprague-Dawley rats were randomly divided into normal control group (C), model group (M) and puerarin group (P). The mean of carotid arterial pressure (mCAP), mean of left ventricular end diastolic pressure (LVEDP), and the weight ratio of left ventricular mass (left ventricle plus septum) to bodyweight (LVM/BW) were measured to evaluate the model of 2K1C renal hypertension. The concentrations of apelin in the plasma and left ventricle (LV) were measured with radioimmunoassay. Apelin mRNA and APJ mRNA expressed in the LV were examined by reverse transcription-polymerase chain reaction (RT-PCR). The peptides of apelin and APJ expressed in the LV were detected with immunohistochemistry (IHC).

RESULTCompared with C group, the mCAP, LVEDP and LVM/BW of M group were higher 36.58%, 333.8% and 20.24%, respectively (P<0.05, P<0.01, P<0.01). Compared with M group, LVEDP and LVM/BW of P group were lower 65.24% and 13.12%, respectively (both P<0.05). However mCAP was of no significant difference between these two groups. The levels of apelin-36 in the plasma and LV of M group were respectively higher 18.56% and 207.38% than those of C group (both P<0.05), while ones of P group were lower 24.21% and 49.40% than those of M group (both P<0.05). The expressions of apelin mRNA and APJ mRNA at left ventricle tissues of 2K1C rats were higher 77.66% and 119.00% (both P<0.05) than those of C group. The ones of P group were lower 27.40% and 45.66% than those of M group (both P<0.01). The IHC results indicate that the expressions of apelin and APJ peptides at left ventricle tissues of 2K1C rats were higher 129.51% and 154.1% (both P<0.01) than those of C group, respectively. Whereas the ones of P group were lower 65.36% and 62.87% than those of M group (both P<0.01).

CONCLUSIONThrough regulating apelin/APJ system puerarin has protective effect on the development of left ventricular hypertrophy by renal hypertension.

Animals ; Apelin ; Apelin Receptors ; Carrier Proteins ; genetics ; metabolism ; Gene Expression ; drug effects ; Hypertension, Renal ; drug therapy ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; prevention & control ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins ; Isoflavones ; therapeutic use ; Male ; Radioimmunoassay ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVETo assess the effect of angiotensin II type 1 (AT(1)) receptor antagonist losartan on myocardium connexin43 (Cx43) gap junction (GJ) expression in spontaneously hypertensive rats (SHRs) and investigate possible mechanisms.

METHODSSixteen 9-week-old male SHRs and 8 age-matched male Wistar-Kyoto (WKY) rats were included in this study. SHRs were randomly divided into two groups to receive losartan at 30 mg/(kg x d) by oral gavage once daily for 8 weeks (SHR-L) or vehicle (0.9% saline) to act as controls (SHR-V); WKY rats receiving vehicle for 8 weeks served as normotensive controls. At the end of the experiment, rats were sacrificed and the hearts were removed. Expressions of Cx43 and nuclear factor-kappaB p65 (NF-kappaB p65) proteins in all three groups were observed and further investigations on the effect of angiotensin II type 1 receptor antagonist losartan (30 mg/(kg x d), 8 weeks) on Cx43 expression were conducted with Western blot and immunohistochemistry. NF-kappaB p65 protein in nuclear extracts was determined by Western blot.

RESULTSLeft ventricular (LV) hypertrophy was prominent in SHRs, Cx43 and NF-kappaB p65 protein expressions were obviously upregulated and Cx43 distribution was dispersed over the cell surface. Treatment with losarton reduced the over-expressions of Cx43 and NF-kappaB p65 in LV myocardium. The distribution of Cx43 gap junction also became much regular and confined to intercalated disk after losartan treatment.

CONCLUSIONCx43 level was upregulated in LV myocardium of SHR during early stage of hypertrophy. Angiotensin II type 1 receptor antagonist losartan prevented Cx43 gap junction remodeling in hypertrophied left ventricles, possibly through the NF-kappaB pathway.

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Animals ; Blood Pressure ; drug effects ; Blotting, Western ; Connexin 43 ; metabolism ; Hypertension ; drug therapy ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; drug therapy ; metabolism ; pathology ; Losartan ; pharmacology ; Male ; Myocardium ; metabolism ; Natriuretic Peptide, Brain ; blood ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Transcription Factor RelA ; metabolism

OBJECTIVETo investigate the effect of PPAR alpha activator fenofibrate on left ventricular hypertrophy and myocardium PPAR alpha (peroxisome proliferator-activated receptor-alpha) expression in spontaneously hypertensive rats (SHR).

METHODSSixteen nine-week-old male spontaneously hypertensive rats were randomly divided into two groups: SHR received fenofibrate 100 mg x kg(-1) x d(-1) by oral gavage once daily for 8 weeks (SHR-F, n=8), and SHR received vechile (0.9 % saline) acted as controls (SHR, n=8). Age-matched Wistar-kyoto rats received vehicle for 8 weeks were served as negative controls (WKY, n=8). Systolic blood pressure was measured at the beginning, 2, 4, and 8 weeks of the experiment. At the end of the experiment, plasma BNP (brain natriuretic peptide)and lipid levels were measured. Left ventricular hypertrophy was accessed by pathological analysis. The expression of PPAR alpha and nuclear factor-kappa B (NF-kappa B p65) were investigated by the method of Western blotting.

RESULTCompared with SHR group, systolic blood pressure was slightly lowered in SHR-F group, but it didn't reach significant level(p>0.05). Fenofibrate administration lowered plasma BNP in SHR-F group (P<0.01). There were not much difference of plasma lipid levels between SHR-F and SHR group. Left ventricular mass index (assessed by left ventricular weight/body weight, g x kg(-1)), transdiameter of cardiomyocyte (TDM), cardiomyocyte area (CA), collagen volume fraction (CVF), and perivascular circumferential area (PVCA) decreased significantly in SHR-F group (P<0.05, P<0.01). The myocardium PPAR alpha expression increased significantly (P<0.01), and NF-kappa B p65 expression decreased significantly (P<0.01) in SHR-F group.

CONCLUSIONPPAR alpha activator fenofibrate can regress left ventricular hypertrophy and increase myocardium PPAR alpha expression in spontaneously hypertensive rats, which is perhaps independent of its lipid-lowering activity.

Animals ; Blood Pressure ; drug effects ; Blotting, Western ; Fenofibrate ; therapeutic use ; Hypertension ; drug therapy ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; blood ; drug therapy ; metabolism ; Lipids ; blood ; Male ; Myocardium ; metabolism ; Natriuretic Peptide, Brain ; blood ; PPAR alpha ; biosynthesis ; Random Allocation ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Time Factors ; Transcription Factor RelA ; biosynthesis

BACKGROUNDConnexin43 (Cx43) is the predominant gap junction protein in heart and is involved in the control of cell-to-cell communication to modulate the contractility and the electrical coupling of cardiac myocytes. Left ventricular (LV) hypertrophy is accompanied by changes of Cx43 expression. Recent studies have demonstrated that statins reduced cardiac hypertrophy. However, it is unknown whether statins can affect Cx43 expression in hypertrophied left ventricular myocardium. This study was designed to assess the effects of atorvastatin on LV hypertrophy and Cx43 expression in spontaneously hypertensive rats (SHR).

METHODSNine-week old SHRs were randomly divided into two groups. Some received atorvastatin at 30 mg/kg by oral gavage once daily for 8 weeks (SHR-A); others received vehicle. Age-matched Wistar-Kyoto rats (WKY) received atorvastatin or vehicle for 8 weeks were used as controls. At the end of the experiment, we investigated LV hypertrophy and the expression of Cx43 in LV myocardium in four groups. Cx43 expression was investigated by the methods of Western blotting, immunohistochemistry, and transmission electron microscope. LV hypertrophy was accessed by pathological analysis and plasma brain natriuretic peptide (BNP) level.

RESULTSLV hypertrophy was prominent in untreated SHR. In SHR, LV myocardium Cx43 level was upregulated, and the distribution of Cx43 was displaced from their usual locations to other sites at various distances away from the intercalated disks. After atorvastatin treatment, myocardium Cx43 level was reduced in SHR-A, and the distribution of Cx43 gap junction became much regular and confined to intercalated disk. Statins also prevented LV hypertrophy in SHR.

CONCLUSIONSThese results provide novel in vivo evidence for the key role of Cx43 gap junctions in LV hypertrophy and the possible mechanism in anti-hypertrophic effect of statins. Atorvastatin treatment may have beneficial effects on LV hypertrophy in spontaneously hypertensive rats.

Animals ; Anticholesteremic Agents ; pharmacology ; Atorvastatin Calcium ; Blood Pressure ; drug effects ; Blotting, Western ; Connexin 43 ; metabolism ; Heart ; drug effects ; physiopathology ; Heptanoic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Hypertrophy, Left Ventricular ; blood ; drug therapy ; metabolism ; pathology ; Immunohistochemistry ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Male ; Microscopy, Electron, Transmission ; Myocardium ; metabolism ; pathology ; ultrastructure ; Natriuretic Peptide, Brain ; blood ; Pyrroles ; pharmacology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY