一氧化氮与大鼠缺血性急性肾衰竭关系的实验研究

目的 研究一氧化氮（ＮＯ）在缺血性急性肾衰竭病理过程中的作用。方法 通过夹闭大鼠双侧肾蒂４５分钟后再松夹复制出急性肾衰（ＡＲＦ）模型,各组在松夹后分别静滴生理盐水,Ｌ－精氨酸,Ｄ－精氨酸,Ｎ－硝基－Ｌ－精氨酸（ＮＬＡ）。结果 与盐水对照组相比,Ｌ－精氨酸组菊糖清除率和再灌注早期的尿流率增高（Ｐ〈０．０５）,尿钠排泄分数下降（Ｐ〈０．０５）,肾病理损害也较轻（Ｐ〈０．０５）,ＮＬＡ虽升高血压（Ｐ〈０     

Endotoxin-induced acute renal failure in rats: effects of L-arginine and nitric oxide synthase inhibition on renal function

BACKGROUND: The regulation of renal hemodynamics is closely related to the L-arginine (L-Arg)/nitric oxide (NO) pathway. NO - metabolized from L-Arg - is capable of improving renal function in ischemic and toxic acute renal failure (ARF), while NO synthase (NOS) inhibition induces deterioration in renal function. The mortality rate in patients with septic shock is increased when treated with a non-selective NOS inhibitor, while the incidence of ARF requiring renal replacement therapy is unaffected. To date, there are no studies on the impact of NOS substrate (L-Arg) and inhibitor (L-NMMA) on renal function in early lipopolysaccharide (LPS)-induced ARF. METHODS: ARF was induced by intravenous (i.v.) LPS. Animals were treated with L-Arg, L-NMMA (NOS substrate and inhibitor), a combination of both or saline. Glomerular filtration rate (GFR), urine flow, fractional sodium excretion, excretion of NO metabolism stable end products and blood pressure (BP) were recorded at baseline, after ARF induction, during drug infusion and thereafter. RESULTS: L-Arg induced better GFR during infusion. Excretion of the NO metabolism end products was highest in the L-Arg group and lowest in the NOS inhibitor group. L-Arg administration had no influence on BP, while L-NMMA induced a slight elevation. CONCLUSIONS: We conclude that exogenous L-Arg exerts beneficial effects in early LPS-induced ARF in rats during drug infusion, while NOS inhibition has no influence on GFR. Subcellular compartmentalization of the L-Arg pool in cytoplasma and the rapid utilization of exogenous L-Arg in such a micro-environment could explain this effect, which has been observed in other ARF models and was called the "L-Arg paradox". In further studies the effects of early and prolonged administration of L-Arg in endotoxinemia should be investigated.     

L-Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats

BACKGROUND: In ischemic acute renal failure (ARF), nitric oxide-dependent regulation of renal hemodynamics and glomerular function is disturbed. Previous studies indicate that the nitric oxide precursor l-arginine (l-Arg) has beneficial effects on renal function. Here we further analyzed the impact of l-Arg on functional and biochemical parameters of nitric oxide signaling during the course of ischemic ARF. METHODS: Ischemic ARF was induced in rats by bilateral clamping of renal arteries for 45 minutes. l-Arg was applied intraperitoneally during clamping, and orally during 14 days of follow-up. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured, and biochemical parameters analyzed by protein immunoblots. RESULTS: Clamping resulted in 70% to 90% reduction of GFR and RPF, with a gradual recovery by day 14. Using an in situ assay with the oxidative fluorescent dye hydroethidine, increased tubular generation of O2- was detected in the early course of ischemic ARF, indicating enhanced oxidative stress. These findings were accompanied by up-regulation of the nitric oxide receptor, soluble guanylate cyclase, and by significant regulatory changes of inducible nitric oxide synthase (iNOS) and endothelial NOS expression. l-Arg had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of iNOS. CONCLUSION: Ischemic ARF is accompanied by marked alterations in the expression of key enzymes of the nitric oxide pathway, indicative for deficiency of constitutive NOS activity. l-Arg supplementation reduces O2- generation and significantly improves the expression of nitric oxide signaling proteins as well as the recovery phase of ischemic ARF.     

Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation

Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.     

一氧化氮供体防治急性缺血性肾衰的实验研究

为了进一步证实一氧化氮（ＮＯ）在急性缺血性肾衰（ＩＡＲＦ）发生发展中的作用，采用ＮＯ供体ＳＩＮ１对大鼠ＩＡＲＦ模型进行腹主动脉持续灌注３小时。结果发现：ＮＯ供体输入体内可在肾内迅速产生高浓度ＮＯ，可明显改善肾缺血再灌注后的肾皮质缺血，减轻肾功能及组织学损害。结果表明：ＮＯ下降参与了缺血再灌注的肾功能损害，是ＩＡＲＦ发生发展的重要因素之一。ＮＯ缺乏主要导致肾血流量下降，继而ＧＲＦ下降。应用ＮＯ供体直接提供外源性ＮＯ，提高肾内ＮＯ水平可以有效增加肾缺血再灌流后肾血流，改善肾功能，是防治ＩＡＲＦ又一新途径。     

一氧化氮和一氧化氮合成酶在急性肺损伤的作用

急性肺损伤(acute lung injury,ALI)是一种发病率和死亡率都很高的常见临床疾病. 目前,对ALI病理生理学基础和临床研究方面的了解越来越多,但并没有提出新的治疗策略能够明显改善ALI的治疗.在ALI的动物模型和患者中,一氧化氮合成酶(nitric oxide synthases,NOS)表达及活性增强和一氧化氮(NO)的增多在ALI的病理生理过程中有重要作用;但临床抑制NO生成以及选择性抑制NOS并没有对ALI的治疗有明显效果.目前提出了不同细胞源性NO的概念,这种NO的细胞源性差异可能对ALI的治疗有潜在的意义.现综述NO和NOS在ALI中的作用.     

Tubular and Glomerular L-Arginine Transport (Uptake and Transporters) and the Nitric Oxide Synthases in Ischemic Acute Renal Failure (iARF) in Streptozotocin-Induced Diabetic Rats (STZ-DM)

Background. L-arginine or its metabolites may be important pathogenetic factors in ischemic acute renal failure (iARF) in rats. It was found that the L-arginine-nitric oxide synthase-nitric oxide system plays an important role in the renal hemodynamic alterations in the early stages of diabetes. The iARF in diabetic rats is much more severe than the normal rats exposed to a same ischemia time. The purpose of the present study was to evaluated L-arginine uptake and its transporters and nitric oxide synthase isoform expression in tubuli and glomeruli of STZ-induced diabetic rats with iARF. Methods. iARF was induced by right nephrectomy and left renal artery clamping for 60 min followed by a 60 min reflow period. iARF was induced in STZ diabetes rats two weeks after intraperitoneal streptozotocin (60 mg/kg body weight) and in normal control rats. L-arginine uptake, L-arginine transporters (CAT1 and CAT2) and nitric oxide synthases (iNOS, eNOS, and bNOS) were determined by RT-PCR) in both glomeruli and tubuli preparations. Results. The STZ diabetic rats compared with the non diabetic normal rats have a higher glomerular L-arginine uptake, higher iNOS mRNA, lower eNOS mRNA, and lower tubular CAT1 mRNA, eNOS mRNA, and bNOS mRNA. The diabetic iARF after one hour of reperfusion had lower glomerular L-arginine uptake, lower CAT1 mRNA, lower eNOS mRNA, lower bNOS, and higher tubular iNOS mRNA compared with iARF in normal rats.

Conclusions. Our findings suggest a prolonged and more severe post-glomerular vasoconstriction very early after the reflow in the iARF of STZ diabetic rats compared with the iARF in the normal control rats. That may be a plausible explanation to the very significant decline in GFR and tubular necrosis that characterize the iARF in diabetic rats.     

Role of the L-arginine/nitric oxide pathway in renal ischaemia-reperfusion in rats.

OBJECTIVE: To study the role of the L-arginine/nitric oxide (NO) pathway during renal ischaemia-reperfusion in rats. DESIGN: Randomised experimental study. SETTING: Teaching hospital, Brazil. ANIMALS: 97 male Wistar rats randomly assigned to 4 groups for the assessment of renal dysfunction and to 6 groups for the assessment of the oxidative stress induced on renal cell membranes by ischaemia-reperfusion. INTERVENTIONS: The animals underwent sham-operation or renal ischaemia-reperfusion (n = 9 each) with or without pretreatment with L-arginine (a NO donor) or L-NAME (N(omega)-nitro-L-arginine methyl ester--an inhibitor of NO production) (n = 10 each). MAIN OUTCOME MEASURES: Serum creatinine concentrations and oxidative stress by chemiluminescence initiated by the tert-butyl hydroperoxide technique. RESULTS: Renal ischaemia-reperfusion significantly worsened renal dysfunction and increased oxidative stress in the ischaemia-reperfusion group after 24 and 96 hours of reperfusion compared with the control group (p < 0.05). Pretreatment with L-NAME slightly but not significantly increased serum creatinine concentrations after 24 and 96 hours of reperfusion together with activity of reactive oxygen species during renal ischaemia-reperfusion. L-arginine also significantly protected renal function and reduced the increment in the amount of chemiluminescence induced by giving L-NAME during 24 and 96 hours of reperfusion (p < 0.05). CONCLUSION: The L-arginine/NO pathway seems to have a slightly protective effect on the kidney after renal ischaemia-reperfusion injury in rats. These results need to be confirmed by studies in human beings.     

Melatonin reduces nitric oxide via increasing arginase in rhabdomyolysis-induced acute renal failure in rats

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger. In addition to a direct scavenging effect on nitric oxide (NO), its inhibitory effect on nitric oxide synthase (NOS) activity has been also reported. L-arginine is the substrate for both NOS and arginase. It has been suggested that there is a competition between arginase and NOS and that they control each other's level. NO plays a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). In this study, the authors aimed to investigate the effect of melatonin on arginase activity, ornithine, and NO levels on the myoglobinuric ARF formed by intramuscular (i.m.) injection of hypertonic glycerol. Forty rats were randomly divided into four groups. Rats in SHAM were given saline, and those in groups ARF, ARF-M5, and ARF-M10 were injected with glycerol (10 mL/kg) i.m. Concomitant and 24 hours after glycerol injection for the ARF-M5 and ARF-M10 groups, melatonin--5 mg/kg and 10 mg/kg, respectively--was administrated intraperitoneally. Forty-eight hours after the glycerol injection, kidneys of the rats were taken under anesthesia. Arginase activity, ornithine, and NO levels in the kidney tissue were determined. Melatonin had an increasing effect on kidney tissue arginase activities and ornithine levels while decreasing NO concentration. It is possible that besides the direct scavenging effect, the stimulatory effect of melatonin on arginase activity may result in an inhibition of NOS activity and, finally, a decrease in the kidney NO level.     

Roles of nitric oxide and nitric oxide synthases in tissue damage of obstructed ureters in rats

OBJECTIVE: To investigate the roles of nitric oxide (NO) and NO synthases [endothelial constitutive NO synthase (eNOS) and inducible NO synthase (iNOS)] in the pathogenesis of ureteric damage during the course of obstructive uropathy. MATERIAL AND METHODS: The expression of nitrotyrosine, eNOS and iNOS was studied in 54 Sprague-Dawley rats using immunohistochemistry with concurrent immunohistochemical staining. RESULTS: Hypertrophy and fibrotic changes of the smooth muscle of the obstructed ureters were noticed after ureteric ligation. The expression of iNOS, eNOS and nitrotyrosine in the smooth muscle layer was noticed from Days 7, 10 and 14 after ligation, respectively, increased until Day 21 post-ligation and then decreased. The expression of nitrotyrosine in the smooth muscle layer was significantly correlated with the expression of iNOS and eNOS (r=0.9698 and 0.9683, respectively; p<0.0001 for both). CONCLUSION: NO and NO synthases may play important roles in tissue damage of the smooth muscle layer in obstructed ureters.     

Fucoidin, an inhibitor of leukocyte adhesion, exacerbates acute ischemic renal failure and stimulates nitric oxide synthesis

OBJECTIVES: To lessen renal ischemic injury caused by fucoidin, a substance capable of reducing tissue infiltration by neutrophils, and to seek a possible interrelationship with the nitric oxide system which may also modulate leukocyte infiltration. MATERIAL AND METHODS: Acute ischemic renal failure was induced in rats by uninephrectomy followed by 60 min of clamping of the renal artery. The rats were injected with fucoidin (25 mg/kg) or fucoidin+nitroprusside (2.5 mg/kg) before reperfusion, and urine was collected for 24 h afterwards. Serum and urine were examined for creatinine sodium and protein; creatinine clearance and fractional excretion of sodium (FENa) were calculated. The renal tissue of the sacrificed animals was examined histologically for tissue damage and histochemically for myeloperoxidase, a marker of neutrophil infiltration. The nitric oxide system was evaluated by measuring urinary nitrates and inducible nitric oxide synthase messenger RNA (iNOs mRNA). RESULTS: Renal failure was more severe in the fucoidin group than the nitroprusside group (creatinine clearance 0.11+/-0.08 ml/min for ischemia+fucoidin versus 0.26+/-0.11 ml/min for ischemia only; p<0.002). Adding nitroprusside to fucoidin lessened the decline in creatinine clearance (0.13+/-0.13 ml/min; p=NS). Fucoidin was associated with greater tubular damage, as evidenced by increased FENa (7.2%+/-2.8% vs 1.51%+/-1.96% for ischemia only; p<0.001). Nitroprusside weakened this trend. Fucoidin caused an increase in the fractional excretion of nitrates, a response accompanied by increased iNOS mRNA. CONCLUSIONS: Fucoidin failed to protect the kidney from ischemic damage and was even nephrotoxic. It also stimulated the formation of iNOS RNA.     

Atorvastatin improves the course of ischemic acute renal failure in aging rats

Statins increase the production of nitric oxide (NO) and have beneficial effects on the course of acute renal failure (ARF) in young rats. The effects of a short-term treatment with atorvastatin (ATO) on ischemic ARF in old rats, characterized by a great susceptibility to ischemia, was tested. No difference was found in renal dynamics between young (Y, 3 mo old) and old (O, 18 mo old) rats in normal conditions (CON) or after ATO treatment (12 mg/kg/d for 14 d). Twenty-four hours after clamping of both renal arteries, a more pronounced decrease in GFR was observed in O rats versus Y rats after a greater renal vasoconstriction and hypoperfusion of aging animals. Pretreatment with ATO mitigated renal vasoconstriction in O rats and restored GFR values to Y rats. Nitrate excretion was enhanced in Y rats after ARF but was not further modified by ATO; in O rats, ARF did not increase nitrate excretion, which was raised after ATO treatment. This reflected the increase in endothelial NO synthase (eNOS)-mRNA expression and eNOS protein observed in old ATO-treated animals with ARF. ATO treatment had also a significant protective effect against the cell injury at tubular level in O, but not Y, rats. The Ras system was not influenced by ATO in O rats, whereas the activation of Rho proteins was partially inhibited by ATO. Low-dose treatment with ATO enhances NO availability in aging rats, improving renal dynamics and conferring a peculiar histologic protection at tubular level after ischemia.     

The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats

BACKGROUND: Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy. METHODS: Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release. RESULTS: STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, d-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides. CONCLUSION: Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.     

L-Arginine transport is augmented through up-regulation of tubular CAT-2 mRNA in ischemic acute renal failure in rats

BACKGROUND: Ischemic acute renal failure (iARF) is associated with increased nitric oxide (NO) production during the reperfusion period, as endothelial nitric oxide synthase (eNOS) is maximally activated, and renal tubular inducible NOS (iNOS) is stimulated. Increased NO production leads to augmented tubular injury, probably through the formation of peroxynitrite. l-Arginine (l-Arg), the only precursor for NO, is transported into cells by cationic amino acid transporters, CAT-1 and CAT-2. We hypothesized that the increased NO production observed in iARF may result from increased l-Arg uptake, which would be reflected in the augmented expression of l-Arg transporter(s). METHODS: Ischemic acute renal failure was induced in rats by right nephrectomy + left renal artery clamping for 60 minutes. l-Arg uptake was examined in freshly harvested glomeruli and tubuli from control, sham operated, and animals subjected to 15, 30, and 60 minutes, and 24 hours of reperfusion, following 60 minutes of ischemia. Using RT-PCR, renal tissues were examined further for the expression of iNOS, CAT-1, CAT-2, arginase I and arginase II. RESULTS: Tubular expression of iNOS mRNA was initiated by ischemia, continued to increase after 60 minutes of reperfusion, and decreased after 24 hours. l-Arg transport into glomeruli was similar in all experimental groups. l-Arg uptake into tubuli was markedly augmented following the 60-minute reperfusion, while it moderately increased after 24 hours of reperfusion. This was accompanied by a parallel, preferential increase in tubular CAT-2 mRNA expression at 60 minutes of reperfusion. CAT-1 mRNA expression was unchanged, as detected by RT-PCR. In addition, the expression of arginase II and arginase I mRNA was attenuated by 30 minutes and one hour of reperfusion, and returned to baseline values after 24 hours of reperfusion. CONCLUSIONS: Ischemic ARF is associated with augmented tubular CAT-2 mRNA expression, which leads to enhanced l-Arg transport and increased NO production. This may contribute to the renal injury exhibited in iARF.     

Endothelium-dependent vasodilatation produced by the L-arginine/nitric oxide pathway in normal and ischemic bone

We used an experimental model of the perfused isolated rabbit tibia to investigate the vasodilatation produced by nitric oxide in the circulation of bone. Tibiae were perfused at a constant flow rate while the perfusion pressure was monitored continuously. Perfusion pressure was raised by the addition of noradrenaline to the perfusate, and dose responses were measured for bolus doses of acetylcholine and sodium nitroprusside. N^w-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, was then added to the perfusate at a concentration of 10⁴ M, and the dose responses to acetylcholine and sodium nitroprusside were repeated. Measurements were performed on groups of bones after 0, 6, 12, and 24 hours of normothermic ischemia (n 5,4,6, and 9, respectively). Both acetylcholine and sodium nitroprusside produced significant vasodilatation after 0 and 6 hours' ischemia, but no significant response was observed after 12 or 24 hours of ischemia. The vasodilatation produced by acetylcholine was significantly attenuated when L-NAME was added to the perfusate, but the vasodilatation produced by sodium nitroprusside remained unchanged. These findings confirm endothelial production of NO by stimulation of muscarinic receptors on the endothelial cells in bone and indicate that vasodilatation via the L-arginine/NO pathway remains viable for 6 hours after normothermic ischemia.     

洛沙坦对糖尿病大鼠肾组织一氧化氮水平的影响

目的 研究洛沙坦对糖尿病大鼠肾组织一氧化氮（NO）水平的影响。方法 雄性Wistar大鼠分为3组,A组（11只）为正常对照组,B组（11只）为糖尿病未干预组,C组（9只）为糖尿病大鼠洛沙坦干预组。以链脲菌素制备糖尿病大鼠模型,大鼠饲养18周后取出肾脏检测诱导型NO合成酶（iNOS）mRNA的表达,电镜检测大鼠肾小球基底膜厚度及系膜基质密度（系膜基质面积/系膜面积）。收集24h尿测定尿白蛋白排泄（UAE）及肌酐,并心脏内取血检测血肌酐。mRNA表达采用RT-PCR,以β-actin作为内对照。UAE测定采用大鼠白蛋白特异的酶免疫分析试剂盒。结果 肾组织iNOSmRNA表达在B组大鼠（0.30±0.12）显著高于A组（0.12±0.04,P<0.01）,C组（0.25±0.14）与B组比较差异无显著性意义（P>0.05）。肾组织NO水平在B组大鼠[（0.56±0.20）μmol/mg肾组织]显著低于A组[（1.05±0.25）μmol/mg肾组织]和C组[（1.13±0.62）μmol/mg肾组织,P均<0.01]。UAE在B组大鼠[（2.18±1.98）mg/d]显著高于A组[（0.41±0.47）mg/d]和C组[（0.65±0.89）mg/d,P均<0.05]。肌酥清除率在B组大鼠[（19.75±9.60）ml/d]显著低于A组[（59.63±22.75）ml/d]和C组[（40.88±25.57）ml/d,P均<0.05]。基底膜厚度在B组大鼠[（531.6±107.6）nm]显著高于A组[（312.4±25     

The effects of transdermal insulin treatment of streptozotocin-induced diabetic rats on kidney function and renal expression of glucose transporters

Abstract

The tight glycemic control required to attenuate chronic complications in type 1 diabetes mellitus requires multiple daily injections of bolus insulin which cause hyperinsulinemic edema and hypertension due to Na⁺ retention. Reports indicate that pectin insulin (PI)-containing dermal patches sustain controlled insulin release into the bloodstream of streptozotocin (STZ)-induced diabetic rats. This study investigated whether PI dermal patches can improve the impaired renal function in diabetes. PI patches were prepared by dissolving pectin/insulin in deionized water and solidified with CaCl₂. Short-term (five weeks) effects of thrice daily treatments with PI patches on renal function and urinary glucose outputs were assessed in diabetic animals. Blood and kidney samples were collected after five weeks for measurements of selected biochemical parameters. Blood was also collected for insulin measurement 6?h following treatments. The low plasma insulin concentrations exhibited by STZ-induced diabetic rats were elevated by the application of insulin-containing dermal patches to levels comparable with control non-diabetic rats. Untreated STZ-induced diabetic rats exhibited elevated urinary glucose, K⁺ outputs and depressed urinary Na⁺ outputs throughout the 5-week period. Treatment with PI dermal patches increased urinary Na⁺ output and reduced urine flow, urinary glucose and K⁺ excretion rates in weeks 4 and 5. PI dermal patches increased GFR of diabetic rats with concomitant reduction of plasma creatinine concentrations. Transdermal insulin treatment also decreased the renal expressions of GLUT1 and SGLT1 of STZ-induced diabetic rats. We conclude that PI dermal patches deliver physiologically relevant amounts of insulin that can improve kidney function in diabetes.     

Docosahexaenoic acid ameliorates murine ischemic acute renal failure and prevents increases in mRNA abundance for both TNF-alpha and inducible nitric oxide synthase

This study demonstrates that intraperitoneal injections of DHA (all cis 4,7,10,13,16,19 docosahexaenoic acid C22: n-3) bound to bovine serum albumin ameliorate murine acute renal failure (ARF) induced by temporary occlusion of the renal artery. Three micromoles of DHA decreased serum creatinine (Scr) from 2.3 mg/dl to 1.1 mg/dl 24 h after reperfusion (n = 15; P < 0.05). Scr of the treated animals were significantly lower than controls throughout a 7-d time course. Although lower doses of DHA were less effective, higher doses were not more effective. Ribonuclease (RNase) protection assays showed that ischemia increased mRNA abundance for TNF-alpha and inducible nitric oxide synthase (iNOS) at 24 h. This increase was prevented by DHA administration. Because TNF-alpha and iNOS contribute to renal ischemic injury, their inhibition may contribute to DHA's salutary effect. In addition, the data may have therapeutic implications, because the DHA improves ARF even when administered at 4 h after reperfusion.     

卡托普利和氯沙坦对缺血性急性肾衰竭大鼠肾功能的保护作用

本研究观察卡托普利及氯沙坦干预对缺血性急性肾衰竭(IABF)大鼠肾功能的改善作用.     

Renal blood flow, glomerular filtration rate, and renal morphology in cyclosporine-induced acute renal failure in Munich-Wistar rats

The mechanism of clinical cyclosporine nephrotoxicity has remained unclear. We have established an animal model of cyclosporine-induced acute renal failure in the male Munich-Wistar rat by giving four daily doses of parenteral cyclosporine 60 mg/kg intraperitoneally (IP). In this model, 20 minutes of bilateral renal ischemia preceding the first cyclosporine dose did not significantly increase the renal failure, but did increase mortality (65% v 17%), which was due in part to the CNS effect of cyclosporine. Pair-fed and pair-watered vehicle and saline controls were used. The renal morphologic changes induced by the castor oil vehicle of the commercial parenteral cyclosporine solution were quantitatively similar to those induced by cyclosporine, although the severity of the changes by light microscopy was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum were also seen in other groups. Renal blood flow determined by electromagnetic flow probe showed a significant decline during 2 hours after a single IP injection of cyclosporine (6.6 +/- 0.4 to 5.0 +/- 0.6 mL/min). A similar decline was seen following injection of the castor oil vehicle of the commercial cyclosporine parenteral preparation (6.6 +/- 0.5 to 5.1 +/- 0.5 mL/min), but not after an injection of a similar volume of mineral oil (6.7 +/- 0.3 to 6.3 +/- 0.2 mL/min). These studies suggest that brief renal ischemia does not increase cyclosporine nephrotoxicity significantly in this rat model.(ABSTRACT TRUNCATED AT 250 WORDS)