Effects of dexamethasone on late radiation injury following partial-body and local organ exposures.

Dexamethasone was evaluated as a treatment for radiation-induced lung, kidney, liver, and spinal cord injuries in rats. One experimental group was partial-body-irradiated (22.5 Gy) with the head, femur, and exteriorized intestine shielded to prevent acute mortality. Other animals received local irradiation to the kidney (20 Gy), liver (25 Gy), or a 1-cm segment of cervical spinal cord (18 to 40 Gy). Following irradiation half of the animals in each radiation group were given drinking water containing 188 micrograms/liter of dexamethasone. Tests were done to assess kidney function (hematocrit, plasma urea nitrogen, ethylenediaminetetraacetic acid clearance), liver function (rose bengal clearance, plasma glutamic oxaloacetic acid transaminase), or spinal cord injury (paralysis). The effectiveness of dexamethasone in preventing radiation injury was tissue specific. Dexamethasone eliminated lethal pleural fluid accumulation after partial-body irradiation and delayed development of kidney dysfunction after local kidney irradiation. As a result, dexamethasone increased the median survival time from 63 to 150 days after partial-body irradiation and from 126 to 175 days after local kidney irradiation. After whole-liver irradiation, development of hepatic functional injury was retarded by dexamethasone treatment but without significantly changing survival time. Dexamethasone had no effect on spinal cord tolerance but significantly shortened the latent period between radiation and paralysis.     

Berberine ameliorates renal injury in diabetic C57BL/6 mice: Involvement of suppression of SphK-S1P signaling pathway

Berberine (BBR) was previously found to have beneficial effects on renal injury in experimental diabetic rats. However, the mechanisms underlying the effects are not fully understood. Sphingosine kinase-Sphingosine 1-phosphate (SphK-S1P) signaling pathway has been implicated in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the effects of BBR on renal injury and the activation of SphK-S1P signaling pathway in alloxan-induced diabetic mice with nephropathy. Alloxan-induced diabetic mice were treated orally with BBR (300 mg/kg/day) or vehicle for 12 weeks. BBR inhibited the increases in fasting blood glucose, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. It also prevented renal hypertrophy, TGF-β1 synthesis, FN and Col IV accumulation. Moreover, BBR down-regulated the elevated staining, activity and levels of mRNA and protein of SphK1, and S1P production as well. These findings suggest that the inhibitory effect of BBR on the activation of SphK-S1P signaling pathway in diabetic mouse kidney is a novel mechanism by which BBR partly exerts renoprotective effects on DN.     

Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy.

OBJECTIVE--To assess whether inhibition of angiotensin converting enzyme protects kidney function in diabetic nephropathy. DESIGN--Open, randomised follow up study of normotensive insulin dependent diabetics with nephropathy either treated or not with captopril for one year. SETTING--Outpatient diabetic clinic in a tertiary referral centre. PATIENTS--32 Normotensive patients with insulin dependent diabetes complicated by nephropathy who were randomised either to the treatment group (n = 15) or to the control group (n = 17). INTERVENTIONS--The treatment group was given captopril (25-100 mg/day) for 12 months, the average dose during the second six months of the study being 40 mg daily. Controls were not treated. MAIN OUTCOME MEASURES--Albuminuria, arterial blood pressure, and the glomerular filtration rate. RESULTS--Mean arterial blood pressure fell by 3 (SE 2) mm Hg in the captopril treated group and rose by 6 (1) mm Hg in the controls. In addition, albuminuria declined by 11% in the captopril treated group and rose by 55% in the controls, fractional albumin clearance fell by 17% in the captopril treated group and increased by 66% in the controls, and the glomerular filtration rate declined by 3.1 (2.8)ml/min/1.73 m2 with captopril and by 6.4 (3.1) ml/min/1.73 m2 in the controls. CONCLUSION--Inhibition of angiotensin converting enzyme arrests the progressive rise in albuminuria in normotensive insulin dependent diabetics with nephropathy.     

阿魏酸对糖尿病大鼠肾脏足细胞nephrin、podocin蛋白表达的影响

目的：研究阿魏酸（FA）对链脲佐菌素（STZ）致糖尿病大鼠肾脏足细胞损伤的影响,并探讨其可能的机制。方法：雄性SD大鼠尾静脉一次性注射STZ （40 mg/kg,i.v.）,72 h后将血糖高于16.7 mmol/L者视为糖尿病造模成功,将其随机分为模型组、阿魏酸组,每组10只;另取10只雄性SD大鼠作为对照组;阿魏酸组（100 mg/kg,i.g.,qd）,从大鼠血糖升高第5周开始给药,连续8周。测定空腹血糖、体重、肾脏脏器系数、血清尿素氮、肌酐含量;HE染色观察肾组织病理变化;免疫组化测定肾组织nephrin、podocin蛋白表达。结果：与对照组比较,模型组肾脏脏器系数增大,肾功能下降;病理学显示肾脏细胞萎缩,排列不整齐,并伴有间质增生;足细胞nephrin、podocin蛋白表达明显减少,阿魏酸组明显改善上述指标。结论：阿魏酸具有改善STZ致糖尿病大鼠肾脏功能的作用,其机制可能与上调肾脏足细胞nephrin、podocin蛋白表达有关。     

Dietary selenium for the mitigation of radiation injury: effects of selenium dose escalation and timing of supplementation

We recently reported that daily dietary supplementation with 100?μg selenium (a dose exceeding a rat's nutritional requirement by about 33-fold) initiated immediately after total-body irradiation (TBI) and maintained for 21?weeks mitigates radiation nephropathy in a rat model as indicated by blood urea nitrogen (BUN) levels and histopathological criteria (Radiat Res. 2009; 17:368-73). In this follow-up study, we explored the risks and benefits of delaying the onset of supplementation, shortening periods of supplementation, and escalating selenium supplementation beyond 100?μg/day. Supplementation with 200?μg selenium/day (as selenite or seleno-l-methionine) substantially improved the mitigation of radiation nephropathy by lowering BUN levels at 4?months after TBI from 115 to as low as 34?mg/dl and by proportionally lowering the incidence of histopathological abnormalities. Shortening the period of supplementation to 3 or 2?months did not compromise efficacy. Delaying the onset of supplementation for 1?week reduced but did not abrogate the mitigation of radiation nephropathy. Supplementation with 300?μg/day mitigated radiation nephropathy less effectively than 200?μg and was poorly tolerated. Rats that had been given 10?Gy of TBI were less tolerant of high-dose selenium than nonirradiated rats. This reduced tolerance of high-dose selenium would need to be taken into consideration when selenium is used for the mitigation of radiation injury in victims of nuclear accidents or acts of radiological terrorism. The high dose requirements, the pronounced threshold effect, and the superior performance of selenite suggest that the mitigation of radiation nephropathy involves mechanisms that go beyond the induction of selenoproteins.     

Progression of early phase diabetic nephropathy in streptozotocin-induced diabetic rats: evaluation of various kidney-related parameters

Diabetic nephropathy (DN) is one of the serious secondary complications of diabetes, which results in end-stage renal failure. Reports on the progressive nature of early phase DN especially with respect to kidney parameters such as kidney weight, type IV collagen excretion, total kidney and urinary glycosaminoglycans (GAGs) are few. This work was undertaken to determine systematically the progression of early phase DN in relation to various kidney-related parameters for a period of four months. Experimentally-induced diabetic rats were grouped based on fasting blood glucose levels. Various basic and kidney-related parameters such as kidney weight, microalbuminuria, urinary excretion of GAGs and type IV collagen, total kidney GAGs, histopathology, glomerular area and glomerular volume were examined in control and diabetic rats. There was a progressive increase in fasting blood sugar, urine sugar, kidney weight, microalbuminuria, urine glycosaminoglycans, urine type IV collagen, glomerular area and glomerular volume but there was a progressive decrease in kidney glycosaminoglycans. Glomerular sclerotic condition was aggravated with the increase in duration of diabetes from 1 to 4 months. Onset of DN in rats begins subtly after one month of diabetes but gets vitiated and more pronounced at the end of four months.     

STZ诱导糖尿病肾病大鼠模型的建立

目的建立糖尿病大鼠动物模型,探讨其肾脏损害规律。方法用STZ65mg/kg一次性腹腔内注射方式制作糖尿病大鼠模型,设立空白对照组,饲养14周,期间观察大鼠血糖、尿糖及一般情况变化,实验结束时测定血肌酐、尿素氮、尿蛋白、尿白蛋白排泄率,取肾作病理及超微病理检查。结果模型组大鼠出现血肌酐、尿素氮、尿蛋白、尿白蛋白明显升高,出现肾脏肥大,病理显示明显的肾小球、肾小管病变。结论STZ诱导糖尿病大鼠肾脏表现肾小球及小管间质损害,可以用作糖尿病肾病研究的动物模型。     

Effects of gender on kidney function in magnesium-deficient rats

This study investigated the gender differences in the kidney function of magnesium (Mg)-deficient rats. Male and female rats were fed a control diet or a Mg-deficient diet for 21 d. Mg-deficient diet had no significant effect on kidney calcium (Ca) or phosphorus (P) concentration in male rats, while Ca and P concentrations in female rats were significantly higher in Mg-deficient rats than in the control rats. With regard to indicators of kidney function, no significant differences in creatinine clearance and serum urea nitrogen concentration were observed among the groups. Serum albumin concentrations were significantly lower in rats fed the Mg-deficient diet than in rats fed the control diet. In both sexes, urinary albumin excretion was significantly higher in rats fed the Mg-deficient diet than in rats fed the control diet. Gender differences had no significant influence on creatinine clearance, serum urea nitrogen concentration, serum albumin concentration and urinary albumin excretion. These results suggest that gender differences have no effect on kidney function in Mg-deficient rats under the condition used.     

卡托普利与坎地沙坦对老年糖尿病肾病患者肾功能的影响

目的:研究卡托普利联合坎地沙坦对糖尿病肾病患者肾功能的影响及临床疗效。方法:选择2014年5月-2015年5月我院收治的糖尿病肾病患者90例,根据治疗方法不同分为观察组和对照组。对照组给予卡托普利治疗,观察组在对照组基础上加用坎地沙坦治疗。观察并比较两组患者的临床疗效以及治疗前后空腹血糖、血尿素氮、血肌酐、24 h尿蛋白等水平的变化情况。结果:观察组的治疗总有效率为93.3%,对照组的治疗总有效率为84.4%;观察组患者的临床疗效显著高于对照组,但差异并不具有统计学意义(P0.05)。与治疗前比较,两组患者治疗后的空腹血糖、血尿素氮、血肌酐及24 h尿蛋白水平均显著降低,差异具有统计学意义(P0.05);治疗后,观察组患者的空腹血糖、血尿素氮、血肌酐和24 h尿蛋白值均显著均明显低于对照组,差异均具有统计学意义(P0.05)。结论:卡托普利联合坎地沙坦治疗糖尿病肾病较单独采用卡托普利治疗能够更加有效的改善患者的临床症状,保护患者的肾功能,具有较好的临床疗效。     

Change in histone H3 phosphorylation,MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy

Resveratrol has been reported to have a wide variety of biological effects. However, little is known regarding its role on phosphorylation of histone H3, MAP kinase p38, SIR2 and p53 in type I diabetic nephropathy (DN). Hence, the present study was undertaken to examine changes in the above said parameters by resveratrol treatment. Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg/kg, i.p.). DN was assessed by measurements of blood urea nitrogen and creatinine levels. Phosphorylation of histone H3, SIR2, p53 and MAP kinase p38 expression were examined by western blotting. This study reports that treatment of resveratrol prevents the decrease in the expression of SIR2 in diabetic kidney. It also prevents increase in p38, p53 expression and dephosphorylation of histone H3 in diabetic kidney. This is the first report which suggests that protection against development of diabetic nephropathy by resveratrol treatment involves change in phosphorylation of histone H3, expression of Sir-2, p53 and p38 in diabetic kidney.     

Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy

Resveratrol has been reported to have a wide variety of biological effects. However, little is known regarding its role on phosphorylation of histone H3, MAP kinase p38, SIR2 and p53 in type I diabetic nephropathy (DN). Hence, the present study was undertaken to examine changes in the above said parameters by resveratrol treatment. Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg/kg, i.p.). DN was assessed by measurements of blood urea nitrogen and creatinine levels. Phosphorylation of histone H3, SIR2, p53 and MAP kinase p38 expression were examined by western blotting. This study reports that treatment of resveratrol prevents the decrease in the expression of SIR2 in diabetic kidney. It also prevents increase in p38, p53 expression and dephosphorylation of histone H3 in diabetic kidney. This is the first report which suggests that protection against development of diabetic nephropathy by resveratrol treatment involves change in phosphorylation of histone H3, expression of Sir-2, p53 and p38 in diabetic kidney.     

Influence of protein nutrition on dose-survival relationship following rat kidney irradiation

Immediately following unilateral nephrectomy the remaining kidney of juvenile male Sprague-Dawley rats was sham irradiated or irradiated to doses of 14-30 Gy. Following irradiation the animals were placed on isocaloric diets of either 20 or 4% protein. Median life spans for the animals on the low protein diet were significantly increased compared to the median life spans on the 20% protein diet. Serum urea nitrogen (SUN) levels were periodically measured in rats from each of the experimental groups. SUN levels in the irradiated rats fed the 20% protein diet increased significantly over unirradiated controls as a function of time. In contrast animals fed the 4% protein diet showed no significant changes in SUN levels irrespective of the size of radiation dose and time post irradiation. Renal protective factors calculated as the ratio of 80% survival times for animals fed the 20% protein diet compared to animals fed the 4% protein diet can be calculated to be 2.3 at 18 Gy and 2.8 at 22 Gy. Likewise, a SUN protective factor calculated as the ratio of percentage of nonirradiated control SUN values for the two diets (SUN 20% irradiated) (SUN 20% nonirradiated) (SUN 4% irradiated) (SUN 4% nonirradiated) is 2.4 for 18 Gy and 3.9 for 22 Gy.     

Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria.

OBJECTIVE--To assess the effectiveness of angiotensin converting enzyme inhibition in preventing the development of diabetic nephropathy (albuminuria greater than 300 mg/24h). DESIGN--Open randomised controlled study of four years'' duration. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--44 normotensive (mean blood pressure 127/78 (SD 12/10) mm Hg) insulin dependent diabetic patients with persistent microalbuminuria (30-300 mg/24h). INTERVENTIONS--The treatment group (n = 21) was initially given captopril (25 mg/24 h). The dose was increased to 100 mg/24 h during the first 16 months and thiazide was added after 30 months. The remaining 23 patients were left untreated. MAIN OUTCOME MEASURES--Albuminuria, kidney function, development of diabetic nephropathy (albuminuria greater than 300 mg/24 h), and arterial blood pressure. RESULTS--Clinical and laboratory variables were comparable at baseline. Urinary excretion of albumin was gradually reduced from 82 (66-106) to 57 (39-85) mg/24 h (geometric mean (95% confidence interval)) in the captopril treated group, whereas an increase from 105(77-153) to 166 (83-323) mg/24 h occurred in the control group (p less than 0.05). Seven of the untreated patients progressed to diabetic nephropathy, whereas none of the captopril treated patients developed clinical overt diabetic nephropathy (p less than 0.05). Systemic blood pressure, glomerular filtration rate, haemoglobin A1c concentration, and urinary excretion of sodium and urea remained practically unchanged in the two groups. CONCLUSIONS--The findings suggest that angiotensin converting enzyme inhibition postpones the development of clinical overt diabetic nephropathy in normotensive insulin dependent diabetic patients with persistent microalbuminuria.     

糖适平对2 型糖尿病合并糖尿病肾病4 期患者血糖、肌酐清除率及尿蛋白水平的影响

目的:探讨糖适平对2型糖尿病合并糖尿病肾病4期患者血糖、肌酐清除率及尿蛋白水平的影响。方法:选择我院收治的2型糖尿病合并糖尿病肾病4期患者100例,按照用药情况分为糖适平实验组和胰岛素对照组,每组50例。对照组患者给予预混人胰岛素及阿卡波糖片,实验组患者给予糖适平及阿卡波糖片。比较治疗前后两组患者空腹血糖(FBG)、肌酐清除率(CCr)、血清肌酐(SCr)、血尿素氮(BUN)及24小时尿蛋白定量(24 h Upro)水平的变化情况。结果:与治疗前相比,两组患者治疗后空腹血糖、血清肌酐、血尿素氮及24小时尿蛋白定量、肌酐清除率均明显改善,差异具有统计学意义(P0.05),但实验组与对照组比较差异无统计学意义(P0.05)。结论:糖适平对2型糖尿病合并糖尿病肾病4期患者无药物积蓄问题,用于治疗2型糖尿病合并糖尿病肾病4期安全有效。     

Synergetic effect of Andrographis paniculata polysaccharide on diabetic nephropathy with andrographolide

A water-soluble polysaccharide (APP), with a molecular weight of 4.6×10(4)Da, was isolated from Andrographis paniculata and gas chromatography (GC) analysis showed APP was composed of galactose, mannose, fucose, arabinose and rhamnose with molar ratios of 15.4:2.5:4.3:1.5:1.6. The synergetic effect of APP in combination with andrographolide on renal complication in streptozotocin (STZ) induced diabetic mice was investigated. Wistar rats were made diabetic by injection of STZ, and APP and/or andrographolide was administered to diabetic mice for continuous two weeks. APP plus andrographolide not only increased the body weight and creatinine clearance rate (Ccr), but also decreased the levels of serum creatinine, serum urea nitrogen, urinary albumin excretion (UAE), serum urea and blood glucose in diabetic rats, as well as the relative kidney weight. In summary, APP plus andrographolide can improve the metabolic abnormalities of diabetic mice and prevent or delay the progression of diabetic renal complications, which may be useful as a therapeutic agent for inhibiting the progression of diabetic nephropathy.     

Prophylactic role of arjunolic acid in response to streptozotocin mediated diabetic renal injury: Activation of polyol pathway and oxidative stress responsive signaling cascades

Diabetic nephropathy is a common cause for end-stage renal disease. Present study investigated the beneficial role of arjunolic acid (AA) against streptozotocin (STZ) induced diabetic nephropathy in rats. Diabetic renal injury was associated with increased kidney weight to body weight ratio, glomerular area and volume, blood glucose (hyperglycemia), urea nitrogen and serum creatinine. This nephro pathophysiology increased the productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS), enhanced lipid peroxidation, protein carbonylation and decreased intracellular antioxidant defense in the kidney tissue. In addition, hyperglycemia activates polyol pathway by increasing aldose reductase (AR) with a concomitant reduction in Na⁺-K⁺-ATPase activity. Investigating the oxidative stress responsive signaling cascades, we found the activation of PKCδ, PKC?, MAPKs and NF-κB (p65) in the renal tissue of the diabetic animals. Furthermore, hyperglycemia disturbed the equilibrium between the pro and anti-apoptotic members of Bcl-2 family of proteins as well as reduced mitochondrial membrane potential, elevated the concentration of cytosolic cytochrome C and caspase-3 activity. Treatment of AA effectively ameliorated diabetic renal dysfunctions by reducing oxidative as well as nitrosative stress and deactivating the polyol pathways. Histological studies also support the experimental findings. Results suggest that AA might act as a beneficial agent against the renal dysfunctions developed in STZ-induced diabetes.     

前列地尔联合参芪扶正注射液对IgA肾病的临床疗效观察

目的:探讨前列地尔联合参芪扶正注射液治疗Ig A肾病的临床疗效。方法:选取2011年3月~2015年7月于我院就诊的Ig A肾病患者60例,按照随机数字表法将所有患者分为2组,每组各30例。对照组患者给予前列地尔,实验组患者在对照组的基础上联合使用参芪注射液。比较治疗前后两组患者血清胱抑素C、血肌酐、血尿素氮、血浆白蛋白及24小时尿蛋白水平,同时比较治疗结束后两组患者的临床总有效率。结果:治疗前相比,两组患者治疗后的血清胱抑素C、血肌酐、24小时尿蛋白水平均降低(P0.05);血浆白蛋白水平均升高(P0.05),且实验组患者血清胱抑素C、血肌酐、血尿素氮及24小时尿蛋白水平较对照组更低(P0.05),血浆白蛋白水平更高(P0.05)。与对照组相比,实验组患者临床总有效率较高(P0.05)。结论:前列地尔联合参芪扶正注射液能够提高Ig A肾病患者的临床总有效率,可能与升高血浆白蛋白水平有关。     

Contrasting effects of early and late orchiectomy on hypertension and renal disease in fawn-hooded rats

Fawn-hooded (FH) rats, primarily males, develop spontaneous low-renin hypertension associated with reduced urinary excretion of kallikrein as early as 2 months of age, followed by progressive glomerular sclerosis and proteinuria as early as 3 months of age. In the present study we determined the effects of early (5-7 weeks) or late (5 months) orchiectomy on the blood pressure and nephropathy of FH rats, compared to sham-operated (control) FH males. Early orchiectomy reduced significantly the progression of glomerular sclerosis and of proteinuria and ameliorated the hypertension but had no significant effect on excretion of urinary kallikrein. Late orchiectomy, in contrast, had no significant effect on the progression of glomerular sclerosis or proteinuria but did significantly reduce the blood pressure and marginally increase the excretion of urine kallikrein. These results suggest that (a) male sex hormones may play a role in the pathogenesis of hypertension and nephropathy in the FH rats and (b) renal disease in this strain progresses in spite of improvement in blood pressure.     

A model for diabetic nephropathy: advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse

We have previously found progressive diabetic nephropathy in inducible cAMP early repressor (ICER Igamma) transgenic (Tg) mice. The ICER Igamma Tg mouse is an interesting model of sustained hyperglycemia due to its low production of insulin and insulin-producing beta cells. Here in a longitudinal study we further analyzed diabetic nephropathy and structural and functional alterations in other organs, comparing our model with streptozotocin (STZ)-diabetic model mice. The high-dose STZ-diabetic model showed marked variation in blood glucose levels and severe toxicity of STZ in the liver and kidney. The low-dose STZ-diabetic model showed less toxicity, but the survival rate was very low. STZ-diabetic mice had much more variation of glomerular hypertrophy and sclerosis. Furthermore, non-specific toxicity of STZ or insulin injections to maintain optimal blood glucose levels might have another effect upon the diabetic renal changes. In contrast, ICER Igamma Tg mice exhibited a stable and progressive phenotype of diabetic kidney disease solely due to chronic hyperglycemia without other modulating factors. Thus, ICER Igamma Tg mouse has advantages for examining diabetic renal disease, and offers unique and very different perspectives compared to STZ model.