The effect of the elastase on aminonucleoside nephrosis

In this paper, we studied the effect of elastase on aminonucleoside (AN) nephrosis which is considered a model of focal glomerular sclerosis (FGS). Elastase is an enzyme which disintegrates elastin, discovered by Balo, and used in the treatment of arteriosclerosis and hyperlipidemia. It has also been known to improve metabolism of acid mucopolysaccharides, so, this study focused on metabolic improvement. Three groups of male Sprague-Dawley rats were studied and observed at regular intervals; 30, 60, 90 days. The ANE group (AN + elastase) was administered one shot of AN (10 mg/100 g B.W.) during the test interval, while elastase (5 mg/kg B.W.) was injected 5 days/week for the entire test interval. The AN group was administered one shot of AN only. The third group was a control (C). The following results were observed: (1) Focal segmental hyalinosis and sclerosis (FSHS); ANE group was weaker than AN group. (2) Other significant qualifying glomerular changes (vacuolar change and hyaline droplets of the epithelial cells, adhesion, and foam cells); ANE group was weaker than AN group. (3) Anion loss in GBM was shown by a lack of colloidal iron staining under light microscopy, and by a lack of PEI particles under electron microscopy; there was significantly less anion loss with ANE group, than with AN group. The findings suggest that elastase has an affect on the metabolism of acid mucopolysaccharide and collagen in sclerotic lesion, and may restrain the progress of amino-nucleoside nephrosis.     

The effect of pancreatopeptidase E (elastase) on anastomotic intimal thickness in two types of vascular prosthesis

To determine the effects of pancreatopeptidase E (elastase) on anastomotic intimal thickness in vascular prostheses, expanded polytetrafluoroethylene (ePTFE) and Dacron grafts were implanted in the infrarenal aortas of 28 adult mongrel dogs, divided into four groups of seven dogs each according to the type of graft used and whether or not elastase was given. Thus, group E received ePTFE grafts without elastase; group D received Dacron grafts without elastase; group E + Ela received ePTFE grafts with concomitant oral elastase, 8 mg/kg per day; and group D + Ela received Dacron grafts with elastase given at the same dosage as in group E + Ela. Each graft was harvested 4 months following surgery for histologic examination. It was clearly observed that elastase suppressed intimal growth at the proximal and distal anastomoses in the ePTFE grafts (P<0.05), but not in the Dacron grafts. Furthermore, when we measured the smooth muscle cell percent extinction (%E) on microspectrophotometry in the intima within 2 mm of the proximal and distal anastomoses, it was found that elastase reduced intimal smooth muscle proliferation at the anastomosis of the ePTFE grafts, but not the Dacron grafts (P<0.05). These data suggest that elastase suppresses intimal growth by inhibiting smooth muscle cell migration and proliferation in the vascular prostheses of low but not of high porosity.     

Benefical effect of neutrophil elastase inhibitor on renal warm ischemia-reperfusion injury in the rat

Renal ischemia-reperfusion (I/R) injury is a significant problem in renal transplantation. Neutrophils play an important role in renal I/R injury. Several reports have demonstrated that neutrophil elastase derived from the activated neutrophils might play an important role in this injury. We investigated the effect of a neutrophil elastase inhibitor in renal I/R injury. Male Lewis rats (270-320 g) were used in the model. The right kidney was harvested and the left renal artery and vein were clamped at laparotomy. The kidney was reperfused after 90 minutes of ischemia. Neutrophil elastase inhibitor (ONO-5046: 30 mg/kg) was delivered intravenously before ischemia and after reperfusion to prevent neutrophil activation. In the nontreatment I/R group, no hosts survived 4 days. However, after treatment with neutrophil elastase inhibitor, 3 of 10 rats in the I/R group, survived more than 7 days. These results demonstrated that treatment with neutrophil elastase inhibitor ameliorated renal I/R injury.     

The effect of cigarette smoking on rabbit aortic elastase activity

Twenty rabbits were divided into three groups: (1) cage controls, (2) machine controls, and (3) cigarette exposed. The cigarette-exposed group was exposed to two 2-R1 reference cigarettes a day for 6 weeks on a Walton-II (Process and Instruments Corp., Brooklyn, N.Y.) smoking machine. Rabbits in the machine control group were placed in the smoking machine for the same period of time without cigarettes. Cage control animals were not placed in the smoking machine. Aortic elastase was significantly higher in the cigarette-exposed group (21.11 +/- 6.15) compared to both the cage control group (3.11 +/- 1.11) and machine control group (14.66 +/- 4.69). Aortic elastase in the machine control group was significantly higher in smoke-exposed rabbits than in both cage control and machine control rabbits. These data indicate that cigarette smoking increases aortic elastase activity in rabbits. If these data were to be extrapolated to humans, then patients with abdominal aortic aneurysms who smoke may have an accelerated rate of aneurysm growth or earlier rupture or both.     

The effect of renal replacement therapies on serum gastrointestinal system hormones

BACKGROUND: The kidney is a major site for the inactivation, degradation, and clearance of a variety of peptide hormones. It has been shown that the uremia increases or decreases gastrointestinal system (GIS) hormones. Moreover, studies investigating the serum GIS hormones levels in chronic renal failure (CRF) were conducted mainly in a particular period of the renal replacement therapy, and the changes caused by continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) could not be fully demonstrated. In this study, we investigated the effect of CAPD and HD on serum GIS hormones (amylase, lipase, trypsinogen, and gastrin) levels in CRF patients who were diagnosed for the first time. METHODS: Serum amylase, lipase, trypsinogen, and gastrin levels were measured in 36 patients who were just diagnosed with CRF, 22 patients with CAPD and 14 patients with HD. GIS hormones of these patients were measured before treatment and three months from the beginning of CAPD and HD treatment. As the control group, 20 normal healthy cases with well-matched age and gender were used. RESULTS: The mean serum amylase, lipase, secretin, and gastrin levels were found meaningfully decreased according to the beginning values at third months of the CAPD and HD treatment. However, they were higher than control group. CONCLUSION: In patients receiving CAPD or HD as renal replacement therapy, GIS hormone levels were found to be lower, albeit higher than the healthy control group.     

The possible role of granulocyte elastase in renal damage from acute pyelonephritis

During acute inflammatory processes, extracellular release of granulocyte elastase can contribute to subsequent tissue damage. To test our hypothesis that extracellular elastase release during acute pyelonephritis may contribute to subsequent renal parenchymal damage, we compared the intracellular and extracellular activities of the lysozyme elastase of human polymorphonuclear cells (PMN) when incubated in vitro with bacterial strains causing renal infection that led to either renal damage or no damage. Urine bacterial cultures were obtained from patients with acute pyelonephritis (flank pain, costovertebral angle tenderness, fever >38°C, bacteriuria, pyuria, and leukocytosis). Renal damage was demonstrated by cortical scarring on followup intravenous pyelography and/or diminished function on¹³¹iodine hippuran renal scan. Mean extracellular elastase activity (units/PMN) was 0.15 for unstimulated PMN, 0.07 for PMN stimulated by bacteria not associated with renal damage, and 1.20 for the PMN stimulated by strains associated with renal damage. Mean intracellular elastase activity (units/PMN) was 3.73 for unstimulated PMN, 3.48 for PMN stimulated by bacteria not associated with renal damage, and 3.31 for the PMN stimulated by strains associated with renal damage. Extracellular granulocyte elastase activity was thus significantly higher (P=0.0001) in PMN stimulated by bacterial strains associated with renal damage. Extracellular release of elastase may contribute to the pathogenesis of renal damage in pyelonephritis.     

The effect of temporary clamping of the renal vessels on the vascular resistance in rabbit kidneys.

In studies of 45 rabbits, either the renal artery (35 animals), or the renal artery and vein (10 animals) were clamped in situ. The effect of the clamping--of the warm ischemia--on the vascular resistance of the kidney after reestablishment of the circulation was examined in perfusion studies made after removal of the kidneys from groups of 5 animals between 1 and 5 days after revascularization. Resistance patterns were measured during hypothermic perfusion. The results confirm earlier findings that vascular resistance increases in proportion to the duration of warm ischemia up to 60 min, but not thereafter. The renal vascular resistance falls over the days following revascularization, more slowly after longer periods of ischemia. Thus after 60 min of warm ischemia the vascular resistance became normal within 24 hours, but after 180 min of warm ischemia, the normal resistance range was not reached until 96 hours after reestablishment of the circulation. When both the renal artery and the renal vein were clamped, the pattern was the same but much less emphatic. The vascular resistance never attained such high values as seen after clamping of the renal artery alone, and became normal after 24 hours of revascularization, even when the period of warm ischemia was as long as 180 min.     

The effect of renal artery embolization on the results of treating kidney cancer patients]

To analyze the prognosis, 401 renal cancer cases were examined retrospectively and prospectively. There were 157 females and 244 males. Preoperative embolization of the renal artery resulted in longer survival: in stage T3 it increased from 44 to 60%, in stage T4 from 7 to 50%. After palliative nephrectomy the patients' mean survival reached 10.6 months against 16 months following palliative embolization of the kidney. Palliative embolization is thought the most effective intervention in inoperable cases of renal carcinoma.     

Decreased expression of vascular endothelial growth factor in glomeruli of puromycin aminonucleoside nephrosis

Background. Vascular endothelial growth factor (VEGF) is a selective endothelial growth factor which potently enhances microvascular permeability. In the kidney, VEGF mRNA is known to be highly expressed in visceral epithelial cells in glomeruli. However, the physiological role of VEGF in glomerular function and its involvement in the pathogenesis of proteinuria are not clear. The present studies were designed to determine whether altered expression of VEGF mRNA was observed in the course of puromycin aminonucleoside (PAN) nephrosis in rats (a model of human minimal change nephrosis). Methods. The message level of VEGF in isolated glomeruli of PAN nephrosis rats was measured using a ribonuclease protection assay. Results. VEGF expression began to decrease 4 days after PAN injection and could not be detected in the nephrotic stage of PAN nephrosis (on days 8 and 16). In the remission of stage of PAN nephrosis (on day 28), mRNA was restored to the control level. Conclusions. According to our results, a functional defect in the VEGF expression of visceral epithelial cells was observed in PAN nephrosis. VEGF could be a functional marker of visceral epithelial cells, and the loss of normal expression of VEGF after damage to visceral epithelial cells could affect glomerular endothelial cell function in PAN nephrosis. Received: February 25, 1999 / Accepted: August 11, 1999     

Protective effect of urinastatin on ischemic renal injury in rabbits]

Protective effect of urinastatin on ischemic renal injury in rabbits was investigated by urinary enzymes and renal function tests. Ten rabbits were divided into two groups: the control group and urinastatin group administered 50,000 units/kg of urinastatin. The ischemic renal injury model was made by occluding the left renal artery for 60 minutes. Urinary excretions of N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GTP) (U-NAG and U-gamma-GTP), creatinine clearance (Ccr), free water clearance (CH2O), fractional excretion of sodium (FENa) and urine volume (UV) were measured before occlusion of the left renal artery and after reflow. There were no significant differences in the values before occlusion (baseline values) for U-NAG, U-gamma-GTP, Ccr, CH2O, FENa, and UV between the two groups. U-NAG after reflow was increased in the two groups compared with baseline values, and the increase was significantly lower in the urinastatin group than control group. U-gamma-GTP after reflow was also increased in the two groups compared with baseline values, but the change was not significant between the two groups. Ccr and CH2O after reflow were significantly decreased, and FENa and UV were increased in the two groups compared with baseline values. However, no significant differences were observed between the two groups in these four parameters. These results suggest that urinastatin is effective for the protection of the kidney against ischemic damage, especially of the renal tubular cells.     

The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance.

We have previously documented that cyclosporine exerts a direct cytotoxic effect on endothelial cells and causes an increase in renal vascular resistance (RVR) in the rat. In the present study we investigated whether FK506, a novel immunosuppressive agent thought to be less nephrotoxic than CsA, impairs endothelial cell function in vitro and affects RVR in vivo. In vitro eicosanoid release and endothelin release were measured in bovine aortic endothelial cells in culture exposed for 1, 6, and 24 hr to increasing concentrations of FK506 (1 nM to 10 microM) or CsA (0.5, 10 microM). No significant changes in TxB2 and 6-keto-PGF1 alpha (the stable breakdown products of TxA2 and PGI2, respectively) and endothelin release were found after 1 and 6 hr of incubation with all the concentrations of FK506 and CsA considered. FK506 did not affect endothelin release even after 24 hr of incubation. In contrast, cell exposure to CsA was associated with a dose-dependent increase in TxB2, 6-keto-PGF1 alpha, and endothelin release that reached statistical significance after incubation with 10 microM CsA. FK506 did not induce cell detachment or lysis at any concentration and time considered, while 10 microM CsA induced a significant reduction in cell count accompanied by cell lysis. In vivo studies showed that a single i.v. injection of FK506 to rats within a broad range of doses (28 ng/kg to 2.8 micrograms/kg) did not modify RVR. This was true even for a dose as high as 20 mg/kg, while 20 mg/kg CsA caused a dramatic increase in RVR. We conclude that FK506, unlike CsA, does not induce endothelial cell injury in vitro. Whether this explains the differences in renovascular resistance observed in vivo after acute injection of FK506 and CsA is an attractive possibility that needs to be further explored.