| Objective: Hypertensive nephropathy(HP) is one of the complications of primary hypertension. Its early symptom is microalbuminuria, and the progress stage gradually appear higher serum creatinine, blood urea nitrogen, polyuria, nocturia, proteinuria and edema. Data show that hypertension is the second cause induceingchronic renal failure abroad, while following diabetic nephropathy and chronic glomerulonephritis, is the third causes of end-stage renal disease in china. Some studies found that although blood pressure can be controlled, but the kidney damage will continue to develop in the late atage of hypertensive nephropathy,. Along with the advancement in antihypertensive treatment, control the development of kidney damage also become a top priority.Damage of the microvascular endothelial cells caused by local or systemic inflammatory mediators release and oxidative stress plays a vital role in the process of the occurrence of hypertensive nephropathy. Endothelin is one of the strongest endogenous shrink blood vessels polypeptide. Endothelin increas the glomerular capillary pressure and urinary protein leakage when binds to its’ receptors. While calcitonin gene-related peptide(CGRP) has an antagonistic effect by binding to renal vascular bed of calcitonin gene-related peptide receptor. CGRP may cause renal vasodilatation, increase the glomerular filtration area. Reduced nicotinic acid amine adenine dinucleotide phosphate(NADPH) oxidase is the main source of reactive oxygen species(ROS); In of NADPH oxidase is activated to produce a large number of ROS under the pathological state such as infection, stress and high-sugar, involved in oxidative stress, affected the renal hemodynamics and glomerular filtration rate. Salvianolate is a extract of Salvia medicine. It can protect to the kidneys and heart by inhibiting release of the inflammatonrymedia and oxidative stress. However, the mechanism of protection for HP remains unknown. We therefore hypothesized that salvianolate can improve renal function in patients with HP by inhibiting the generation of NADPH oxidase source ROS.The study pairing determination of patients with HP who treated with combination of salvianolate and valsartan, blood pressure, serum creatinine, blood urea nitrogen, serum cystatin C, serum β2-microglobulin, 24 h urinary protein and urinary albumin; ELISA method to detect serum endothelin-1(ET-1), calcitonin gene-related peptide(CGRP) and serum oxidative stress in the process on behalf of factors: NADPH oxidase(nicotinamide vadenine dinucleotide phosphate oxidase, NOX), reactive oxygen species, protein carbonyl, and malondialdehyde(MDA). Compared to the simple application with patients treated with valsartan: ①investigate the protective effect of combination therapy on renal function in patients with HP; investigate the ②mechanism of Salvianolate improve HP’s for HP rational drug use, improving outcomes, providing a new basis.Methods:1 Screening and grouping of cases:Ninety patients with HP were collected at kidney internal medicine of the First Affiliated Hospital of HEBEI NORTH UNIVERSITY from January 2013 to July 2014. Diagnostic criteria of hypertensive nephropathy was based on "Diagnosis and treatment of kidney disease study". Ninety patients were randomized into 2 groups. The control group of 45 patients use of valsartan 80mg/d orally;Combination of salvianolate and valsartan treatment group(combined group) of 45 patients, in addition to the use of oral valsartan 80mg/d at the same time giving intravenous injection salvianolate 100mg/d. The healthy control group is 45 cases. The samples of the serum and urine/24 hour were collected from three groups. All the samples of the HP patients were measured before administration of the following indicators and two weeks after administration;2 Systolic pressure and diastolic pressure;3 Serum creatinine, blood urea nitrogen, serum cystatin C, serum β2-microglobulin;4 24 h proteinuria and microalbuminuria;5 ELISA method to detect serum endothelin-1(ET-1), calcitonin gene-related peptide(CGRP);6 NOX, ROS, protein carbonyls and MDA;7 Experimental data were expressed as mean ± SD, and statistical analysis was performed using SPSS software 17.0. One-way ANOVA was used between groups and Student-Newman-Keuls(SNK) test was used within groups. P< 0.05 was considered significantly different.Results:1 Blood pressureThe combined group before treatment in patients with systolic and diastolic blood pressure were 160.22 ± 8.00 and 97.89 ± 3.74 mm Hg, respectively after treatment was 136.71 ± 6.22 and 83.38±5.19 mm Hg, the blood pressure were significantly reduced after treatment(P < 0.01); And the antihypertensive effect is more obvious than the control group(P < 0.01).2 Renal function and serum biochemical parametersThe level of serum creatinine in the combined group was significantly reduced(pre-treatment 192.75 ± 31.01 umol / L, after treatment 130.37 ± 26.13 umol / L, P <0.01); While the combined group is much better than the control group(146.51 ± 28.48 umol / L, P<0.01). Blood urea nitrogen levels in the combined group was siginificantly lower(pre-treatment 11.17 ± 3.40 mmol/L, after treatment 7.50 ± 2.11 mmol/L, P <0.01); And compared to the control group after treatment(8.36±2.83 mmol/L), there was no significant difference with two groups. The level of serum β2- microglobulin in the combined group is significantly decreased(pre-treatment 7.52 ± 2.24mg/L, after treatment 4.76 ± 1.52 mg/L, P <0.01); However, compared to the control group after treatment(4.99 ± 1.81 mg/L), there was no significant difference with two groups. Serum cystatin C levels in the combined group was siginificantly lower(pre-treatment 2.22 ± 0.55 mg/L, after treatment 1.48 ± 0.52 mg/L, P <0.01); But compared to the control group after treatment(1.52 ± 0.48 mg/L), there was no significant difference with both group.3 ProteinuriaCombined therapy can significantly reduce 24 h proteinuria(pre-treatment 1495.73 ± 317.34 mg/d, after treatment 500.87 ± 204.05 mg/d, P<0.01); And the combinec group was more lower than the control group(795.04 ± 282.68 mg/d, P <0.01). Combinec therapy can significantly reduce microalbuminuria(pre-treatment 99.36 ± 19.48 mg/L, after treatment 30.30 ± 9.14mg/ L, P <0.01); And the combination group was more siginificantly lower than the control group(54.39 ± 14.58 mg/ L, P <0.01).4 Serum ET-1 and CGRPET-1 levels in patients with hypertensive nephropathy was significantly higher than the normal group; Combined therapy can significantly reduce ET-1(pre-treatment 105.32 ± 48.57 ng/L, after treatment 38.98 ± 11.94 ng/L, P <0.01); And the combination group is more lower than the control group(62.18 ± 22.77 ng/L, P <0.01). CGRP levels in patients with hypertensive nephropathy was significantly lower than the normal group; Combined therapy can significantly increace CGRP(pre-treatment 48.79 ± 10.72 ng/L, after treatment 86.62±26.83ng/L, P <0.01); And the combined group was more higher than the control group(68.41±15.38 ng/L, P <0.01).5 Reactive oxygen species(ROS)The level of NOX in the combined group was significantly reduced(pre-treatment 3.12 ± 0.99 U/L, after treatment 1.57 ± 0.78 U/L, P <0.01); And the combined group was more lower than the control group(2.69 ± 1.07 U/L, P<0.05). Combined therapy could significantly reduce ROS(pre-treatment 168.42 ± 14.97 Intensity/L, after treatment 139.15 ± 20.07 Intensity/L, P <0.01); And the combination group is more lower than the control group(150.19±21.49 Intensity/L, P <0.01). Protein carbonyls levels in the combined group is siginificantly reduced(pre-treatment 2.81 ± 0.27 nmol/mg?prot, after treatment 1.76 ± 0.41 nmol/mg?prot, P <0.01); And the combined group was more lower than the control group(2.09 ± 0.32 nmol/mg?prot, P <0.01). Combined therapy can significantly reduce MDA(pre-treatment 1.85 ± 0.15nmol/mg?prot, after treatment 1.15 ± 0.38nmol/mg?prot, P<0.01); And the combined group was more lower than the control group(1.32 ± 0.36 nmol/mg?prot, P <0.01).Conclusion:1 The patients with hypertensive nephropathy befor treatment have significance increased levels of serum NADPH oxidase, reactive oxygen species(ROS), protein carbonyl, malondialdehyde(MDA) than those with the healthy control group; These suggested that is the patients with hypertensive nephropathy have existed obvious oxidative stress.2 By contrast with before treatment, both therapys had been reduced blood pressure in patients with hypertensive nephropathy, improved renal function, and reduced serum ET-1 and multiple indicators of oxidative stress significantly, while both therapys had been increased significantly CGRPlevel. In the combination therapy group, these parameters had been improved more apparent. These results showed that combination of salvianolate and valsartan has a significantly protective effect on hypertensive nephropathy, which may be related by inhibiting NADPH oxidase-derived ROS generation and thus protection of renal microvascular endothelial cells. |
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