Modulation of anti-Thy1 nephritis in the rat by adenine nucleotides. Evidence for an anti-inflammatory role for nucleotidases.

Extracellular adenine nucleotides are considered mediators of inflammation because they modulate functions of neutrophils and platelets. Until now, this role for adenine nucleotides has not been studied in vivo. In particular in the rat kidney, where ATP- and ADPase activity is present in the glomerular basement membrane, studies about the role of nucleotides may increase our understanding of the dynamics of glomerulonephritis (GN). Therefore, we examined effects of adenine derivatives ATP gamma S, ADP beta S and 2chloro-adenosine (2chloro-ADO) in vitro and during anti-Thy1 GN. The in vitro results show that ADP beta S and ATP gamma S are not degraded by glomerular nucleotidases but, on the other hand do stimulate O2- production of peritoneal exudate cells (PEC). In contrast, 2chloro-ADO significantly inhibits O2- production of peritoneal exudate cells. For in vivo studies rats were rendered nephritic by intravenous injection of monoclonal anti-Thy1 IgG (5 mg/kg body weight). Subsequently, rats were treated with saline (group 1, N = 10), 2chloro-ADO (group 2, N = 10), ADP beta S (group 3, N = 10) or ATP gamma S (group 4, N = 10). All analogs (10 mg/kg body weight) were administered both at t = 0 and t = 12 hour. After 24 hours, rats were sacrificed and kidneys were examined histochemically. In an additional group of nephritic rats (N = 5) proteinuria was studied after 2-chloro-ADO treatment. Results show increased intraglomerular platelet aggregation in nephritic rats treated with ADP beta S, whereas 2chloro-ADO inhibits aggregation significantly as compared with nephritic rats receiving saline. The percentage of granulocytes producing O2- is significantly increased in glomeruli after treatment of nephritic rats with ATP gamma S, whereas cell influx itself is not changed. In contrast, 2chloro-ADO inhibits intraglomerular O2- production, which is associated with the complete inhibition of proteinuria in the early phase of anti-Thy1 GN. These data demonstrate significant pro-inflammatory activities of extracellular adenine nucleotides during anti-Thy1 GN suggesting an anti-inflammatory role for glomerular ATP/ADPase, which in concert with 5' nucleotidase converts ATP and ADP to antiinflammatory ADO.     

Nephrotoxic serum nephritis in nude rats: the roles of host immune reactions in the accelerated type.

By immunization with rabbit immunoglobulins and the injection of a subnephritogenic dose of rabbit nephrotoxic serum (NTS), accelerated-type nephrotoxic serum nephritis (NTN) was induced in heterozygous (rnu/+) rats but not in athymic nude (rnu/rnu) rats. By transferring rat antibody against rabbit immunoglobulins, marked proteinuria was induced also in nude rats (202.0 +/- 98.4 mg/day on day 3) as in rnu/+ rats (122.6 +/- 35.3 mg/day on day 3). No marked differences in histological findings could be found between both groups. The most marked increase in the number of intraglomerular infiltrating cells was observed in heterozygous rats indicating that the presence of thymus-derived cells leads to the accumulation of more cells in glomeruli. We conclude that humoral immunity alone is enough to accelerate the pathogenic mechanism which induces glomerular injury with heavy proteinuria in this model.     

Quantitative assessment of the effects of platelet depletion in the autologous phase of nephrotoxic serum nephritis.

The effects of platelet depletion with antibody have been studied in two models of the autologous phase of nephrotoxic nephritis in the rabbit. In the 'telescoped' model (animals pre-immunized to sheep IgG injected with sheep nephrotoxic antibody), platelet depletion did not alter intraglomerular fibrin deposition or evidence of glomerular damage, but did significantly reduce proteinuria during the first 3 days of the 5 day experiment. In the 'passive' model (animals injected with hyperimmune rabbit antiserum to sheep IgG 48 hr after sheep nephrotoxic antibody and killed 3 hr later), platelet depletion was associated with significantly fewer intraglomerular polymorphonuclear leucocytes (PMN), but again did not alter intraglomerular fibrin deposition. The results indicate that platelets are involved in the initiation of glomerular PMN localization in the autologous phase, but that fibrin-induced glomerular injury is platelet-independent.     

The effect of alloxan, and alloxan-induced diabetes on the kidney

Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. Therefore the present study used the "protected" kidney model to prevent one kidney from being exposed to the alloxan while allowing the other to receive the drug immediately. In all experimental animals the right renal hilum was gently occluded for 5 minutes and then released. This was performed prior to the injection of alloxan. Subsequently, the left renal hilum was occluded at the time of, and for 5 minutes after, alloxan administration (40 mg/kg i.v.). The experimental rats were divided into three groups: untreated diabetics, diabetics treated with protamine-zinc-insulin, and alloxan-treated rats that failed to become diabetic. Three groups of controls were included: one group received an equal volume of saline diluent as the experimental rats but no clamping of either renal hilum; another group received the saline and had the left renal hilum occluded for 5 minutes; and a third group had both the right and left renal hila occluded. All animals were followed and sacrificed after 9 weeks. Endogenous creatinine clearance did not change among groups. Alloxan-treated nondiabetic rats displayed marked interstitial nephritis in unprotected kidneys, while protected kidneys were normal. The diabetic state resulted in mesangial proliferation and focal glomerular basement membrane thickening as well as glomerular capillary endothelial abnormalities and visceral epithelial foot-process fusion. The endothelial changes consisted of focal areas showing a reduction in the size of endothelial fenestrae. All glomerular changes were ameliorated by insulin treatment. We conclude: 1) alloxan per se is distinctly nephrotoxic; and 2) the glomerular endothelium and epithelium are involved early in the course of experimental diabetes.     

Unilateral renal disease in the rat. II. Glomerular mesangial uptake of colloidal carbon in unilateral aminonucleoside nephrosis and nephrotoxic serum nephritis.

Unilateral renal disease was produced in rats by left renal perfusion in situ with the aminonucleoside of puromycin or with nephrotoxic serum. The uptake of colloidal carbon by the glomerular mesangium was increased in kidneys perfused with aminonucleoside or nephrotoxic serum compared to contralateral kidneys. The quantities of carbon within the glomerular mesangium remained increased in aminonucleoside perfused kidneys 14 days later. These studies demonstrate that alterations in glomerular mesangial function in aminonucleoside nephrosis and nephrotoxic serum nephritis are related to renal factors rather than differences in host milieu and may be involved in the pathogenesis of the morphologic lesions seen in chronic proteinuria.     

肾炎益气液对肾毒血清性肾炎大鼠肾脏超微结构的影响

目的:观察肾毒血清性肾炎大鼠肾组织超微结构变化及肾炎益气液对该变化的影响。方法: 采用大鼠肾毒血清性肾炎模型,常规电镜制片、染色,观察肾组织超微结构的变化。结果: 注射肾毒血清(NTS)后,病理组大鼠电镜下可见明显的系膜细胞增生,系膜基质增多,毛细血管腔闭塞及上皮下、内皮下电子致密物沉积等多种病理损伤性变化。而肾炎益气液组上述病变有所减轻。结论: 肾炎益气液有不同程度减轻肾小球电镜下病变的作用。     

Potentiation of nephrotoxic serum nephritis in Lewis rats by Freund's complete adjuvant--possible role for cellular immune mechanisms

Lewis rats receiving subnephritic doses of nephrotoxic serum (NTS) showed increased albuminuria and glomerular histopathologic alterations during the autologous phase of nephrotoxic nephritis (NTN) when they received simultaneous footpad injections of Freund's complete adjuvant (FCA). Lymph nodal lymphocytes from such experimental rats showed increased in vitro cellular sensitization to the nephrotoxic IgG as measured by [3H]thymidine incorporation. Such a lymphocyte blastogenesis response was not detected in rats receiving the same doses of FCA or NTS alone. Antibody titers to the nephrotoxic rabbit IgG were not different in the two groups of rats as measured by enzyme-linked immunosorbent assay. The transfer of lymph nodal mononuclear cells from rats with NTN potentiated by FCA, was able to induce albuminuria and glomerular histopathologic alterations in recipients treated with NTS. In the above experimental model FCA appears to potentiate the autologous phase of NTN by cellular immune mechanisms.     

Prostaglandin E1 suppresses macrophage infiltration and ameliorates injury in an experimental model of macrophage-dependent glomerulonephritis.

Prostaglandin E1 (PGE1) suppresses macrophage infiltration and ameliorates injury in an experimental model of macrophage dependent glomerulonephritis. Macrophages are mediators of glomerular injury in models of proliferative glomerulonephritis. We have recently shown that macrophages in glomerulonephritis have low prostaglandin E2 (PGE) generation, and other evidence implicates eicosanoids as regulators of macrophage activation. Here we have studied in rats the effect of 15(s)-15-methyl PGE1 (M-PGE1) on accelerated nephrotoxic nephritis, a model of acute macrophage-dependent glomerular injury. M-PGE1 ameliorated proteinuria (day 4; 61 +/- 13 mg/24 h, n = 9; vehicle treated, 164 +/- 17 mg/24 h, n = 11; P less than 0.002) and glomerular hypercellularity; quantification of infiltrating macrophages by isolating glomerular cells showed reduction in the numbers of macrophages (44 +/- 9/glomerulus; vehicle treated, 119 +/- 15/glomerulus; P less than 0.02) with inhibition of Ia antigen expression on infiltrating macrophages (8 +/- 5%; vehicle treated 25 +/- 4% P less than 0.05). Glomerular binding of nephrotoxic globulin and levels of autologous antibodies were not affected by M-PGE1. Thus the mechanism of suppression involves inhibition of macrophage accumulation and activation. M-PGE1 administered to normal rats did not affect numbers of resident leucocytes (12.6 +/- 1.5/glomerulus; vehicle treated, 13.2 +/- 1.3/glomerulus) or alter Ia antigen expression (4.1 +/- 0.2 Ia + cells/glomerulus; vehicle treated, 3.9 +/- 0.6/glomerulus). This study suggests a therapeutic role for PGE1 in this type of glomerulonephritis, and has implications for the pathophysiology of macrophage-mediated inflammation.     

Masugi nephritis in T cell-depleted state. Influence of adult thymectomy and anti-thymocyte serum.

The effects of surgical removal of the thymus or the administration of antiserum to thymus-derived lymphocytes on the development of Masugi nephritis were investigated in Wistar rats. While thymectomy at weaning (ATx) had no significant effect on the humoral antibody response to injected rabbit IgG, repeated injections of rabbit anti-rat thymocyte serum (ATS) suppressed it remarkably. Both treatments did not show morphological evidences that glomerular inflammation and injury were suppressed in the autologous phase of Masugi nephritis. Glomerular lesions in rats receiving the nephrotoxic serum (NTS) one month after ATx (ATx-1+NTS) appeared to be severer in hypercellularity, mitotic counts, the amount of deposited fibrin-related substances and crescent formation than those in other nephritic groups. Morphological study of ATS+NTS rats revealed that the glomerular changes were nearly equal to those of NTS-injected control rats, in spite of markedly suppressed humoral response to injected rabbit IgG and the absence of host IgG along the glomerular capillary walls.     

Attenuation of anti-Thy1 glomerulonephritis in the rat by anti-inflammatory platelet-inhibiting agents.

Although both ecto-ADPase and prostacyclin (PGI2) inhibit platelets and neutrophils, their action in acute glomerulonephritis is unknown. We tested the PGI2 analog Iloprost and 2chloroadenosine (2Cl-ADO), an analog of adenosine, the end product of nucleotidase activities, during anti-Thy1 nephritis. Rats received anti-Thy1 immunoglobulin G (5 mg/kg body weight, intravenously) and subsequently one subcutaneous injection of either 2Cl-ADO (10 mg/kg body weight; (n = 6) or Iloprost (1 mg/kg body weight; n = 6). Control rats received anti-Thy1 immunoglobulin G with saline (n = 6) or saline alone (n = 6). After 24 hours, kidneys were processed for light-microscopical evaluation. Proteinuria was studied in additional rats. Results showed that both drugs inhibited intraglomerular platelet activation (P < 0.005). 2Cl-ADO also reduced intraglomerular O2- production of neutrophils (P < 0.05), in contrast to Iloprost. Intraglomerular immunoglobulin G deposition, complement activation, neutrophil influx, and myeloperoxidase release were not affected by 2Cl-ADO or Iloprost. However, proteinuria was completely prevented by both drugs. It is concluded that PGI2 and nucleotidases are potentially able to attenuate this form of nephritis by inhibiting platelet activity, whereas nucleotidases also inhibit neutrophil activity in vivo.     

MASUGI NEPHRITIS IN T CELL-DEPLETED STATE

The effects of surgical removal of the thymus or the administration of antiserum to thymus-derived lymphocytes on the development of Masugi nephritis were investigated in Wistar rats. While thymectomy at weaning (ATx) had no significant effect on the humoral antibody response to injected rabbit IgG, repeated injections of rabbit anti-rat thymocyte serum (ATS) suppressed it remarkably. Both treatments did not show morphological evidences that glomerular inflammation and injury were suppressed in the autologous phase of Masugi nephritis. Glomerular lesions in rats receiving the nephrotoxic serum (NTS) one month after ATx (ATx-1+NTS) appeared to be severer in hypercellularity, mitotic counts, the amount of deposited fibrin-related substances and crescent formation than those in other nephritic groups. Morphological study of ATS+NTS rats revealed that the glomerular changes were nearly equal to those of NTS-injected control rats, in spite of markedly suppressed humoral response to injected rabbit IgG and the absence of host IgG along the glomerular capillary walls. ACT A PATH. JAP. 29 : 333 -345, 1979.     

Early and persistent up-regulated expression of renal cortical osteopontin in experimental hydronephrosis.

The mechanical disturbance after unilateral ureteral obstruction (UUO) is a nonimmune stimulus that is capable of eliciting a florid macrophage infiltration of the kidney and subsequent post-inflammatory renal scarring. Osteopontin has potential chemoattractant activity and, for this reason, we delineated the kinetics of its expression in the renal cortex of rats with UUO. Whole body X-irradiation and reversal of UUO were utilized as interventional maneuvers to give additional pathobiological insight into this protein's role in the response of the kidneys to ureteral obstruction. Increased osteopontin mRNA levels in obstructed kidneys versus contralateral unobstructed specimens were evident as early as 4 hours after UUO and steadily increased at 12, 24, 48, and 96 hours after UUO. Both X-irradiation and reversal of UUO failed to significantly modulate renal cortical osteopontin mRNA expression at all of the above time points. Paralleling the increments in renal cortical osteopontin mRNA levels were significant elevations in the cortical renal interstitial macrophage number, which was significantly diminished by previous X-irradiation but not reversal of UUO. Focal labeling of osteopontin was noted in both tubular and Bowman's capsular epithelium in obstructed kidneys as early as 4 hours after UUO, whereas, in the contralateral unobstructed specimens, there was only faint staining in Bowman's capsule. By 96 hours after UUO, obstructed kidneys exhibited intense, diffuse staining for osteopontin in both tubules and Bowman's capsule. Osteopontin's immunolocalization was not modulated by X-irradiation or reversal of UUO. These data support the contention that osteopontin is involved in the accumulation of macrophages within the peritubular and periglomerular interstitium in the obstructed renal cortex.     

The origin of proliferating cells in the glomerulus and Bowman's capsule in nephrotoxic serum nephritis: effects of unilateral renal irradiation.

The origin of proliferating cells in glomeruli and Bowman''s capsules during nephrotoxic nephritis (NTN) in rabbits was studied, using unilateral renal irradiation to suppress glomerular cell division. Left (LI) kidneys received 2400-12,000 rad on Days 1-5 after i.v. nephrotoxic serum (NTS) 1 or 1.5 ml/kg body wt. Renal histology, cell labelling 1 h after a pulse of tritiated thymidine (H3T) (0.5 mCi/kg), and mitotic rate were compared in right non-irradiated (RO) kidneys and LI kidneys. Differences in H3T uptake were not significantly suppressed (P less than 0.05) by 4800 rad whereas mitoses in glomeruli and Bowman''s capsule were not. Glomerular hypercellularity and crescents were equivalent in LI given 4800 rad and in RO kidneys, but fibrin deposition was increased 2-fold in LI kidneys. In control rabbits (no NTS) LI kidneys showed no histological changes. The results suggest that most dividing cells detected in glomeruli and Bowman''s space in NTN are monocytes, and that these cells form a large component of crescents.     

Induced nitric oxide (NO) synthesis in heterologous nephrotoxic nephritis; effects of selective inhibition in neutrophil-dependent glomerulonephritis.

Increased NO synthesis, due to inducible NO synthase (iNOS) activity, is found in macrophage-associated glomerulonephritis. Little is known about NO in neutrophil-dependent immune complex inflammation, and its role remains controversial. We therefore studied early phase heterologous nephrotoxic nephritis (HNTN) induced in rats by nephrotoxic globulin and the effects of selective iNOS inhibition of this model. At 2 h of the model iNOS mRNA was induced and nitrite (NO-2) was generated in glomeruli incubated ex vivo (5.2 +/- 1.0 nmol/2000 glomeruli per 24 h). There were 14.7 +/- 2.2 polymorphonuclear neutrophils (PMN)/glomerulus (normal controls 0.1 +/- 0.1). At 8 h urinary protein was 69 +/- 15.3 (normal controls 0. 6 +/- 0.2 mg/24 h). Peritoneal PMN expressed iNOS and produced significant NO-2 (basal 11.2 +/- 0.3 nmol/106 cells per 24 h). Selective iNOS inhibition with L-N6-(1-iminoethyl)-lysine (L-NIL) in vitro inhibited nephritic glomerular and PMN NO-2 synthesis. In HNTN L-NIL in vivo significantly suppressed elevated plasma NO-2/NO-3 levels (representative experiment: 17 +/- 2 microM, untreated 40 +/- 4 microM, P = < 0.01, normal control 18 +/- 2 microM). This inhibition did not affect leucocyte infiltration into glomeruli or induce thrombosis. There was no consistent effect on proteinuria. This is the first demonstration of glomerular iNOS induction and high output NO production in the acute phase of PMN-dependent acute immune complex glomerulonephritis. Selective iNOS inhibition does not affect the primary mechanism of injury (leucocyte infiltration) in this model.     

Decay-accelerating factor confers protection against complement-mediated podocyte injury in acute nephrotoxic nephritis

SUMMARY: Decay-accelerating factor (DAF or CD55) is one of a set of regulators that function to protect self cells from deposition of autologous C3b on their surfaces. Its relative importance in vivo, however, is incompletely understood. As one approach to address this issue, we induced nephrotoxic serum (NTS) nephritis in wild-type mice and Daf1 gene-floxed mice devoid of renal DAF expression. For these experiments NTS IgG was administered at a dose (0.5 mg iv) that requires complement for glomerular injury. After 18 hours, renal injury was assessed by proteinuria and by histologic, immunohistochemical, and electron microscopic analyses of kidneys. Fifteen normal and 15 DAF-deficient mice were studied. Baseline albuminuria in the Daf1(-/-) mice was 115.9 +/- 41.4 microg/mg creatinine as compared with 85.7 +/- 32.3 microg/mg creatinine in their Daf1(+/+) littermates (p = 0.075). After administration of NTS IgG, albuminuria increased to 2001.7 +/- 688.7 microg/mg creatinine as compared with 799.7 +/- 340.5 microg/mg creatinine in the controls (p = 0.0003). Glomerular histology was similar in Daf1(-/-) and Daf1(+/+) mice, with essentially no infiltrating leukocytes. In contrast, electron microscopy revealed severe podocyte fusion in the Daf1(-/-) mice but only mild focal changes in the controls. Immunohistochemical staining showed equivalent deposition of the administered (sheep) NTS IgG in the Daf1(-/-) and Daf1(+/+) animals. This contrasted with marked deposition of autologous murine C3 in the former and minimal deposition in the latter. The results show that DAF is essential physiologically for protecting glomeruli against autologous complement attack initiated by the classical pathway.     

Complement-independent nephrotoxic serum nephritis in Munich Wistar rats. Immunologic and ultrastructural studies

Immunologic mechanisms of proteinuria and ultrastructural alterations of the slit pore complex and glomerular charge barrier were investigated in Munich Wistar (MW) rats with nephrotoxic serum nephritis. Prior to disease induction, normal MW sera demonstrated 50% of the complement hemolytic activity compared with sera obtained from Sprague-Dawley rats. MW rats were sacrificed prior to, at onset (5 to 6 hours), and during maximal proteinuria (heterologous phase). Immunofluorescence revealed binding of rabbit antirat IgG antibodies in a linear pattern to the glomerular basement membrane (GBM) within 15 minutes postinjection. Complement deposition was not demonstrable in vivo in this model. Immediately after injection of nephrotoxic serum a decreased penetration of the GBM occurred, restricting ferritin to the level of the endothelium in in situ fixed glomeruli. GBM permeability to native ferritin did not increase despite areas of epithelial cell detachment, endothelial cell sloughing, and proteinuria between 2 and 24 hours postnephrotoxic serum injection. Colloidal iron initially decreased staining intensity between 6 and 8 hours, with a major decrease at 24 hours, indicating a loss in glomerular sialoprotein coincident with the onset of proteinuria. Polyethyleneimine (PEI) localization revealed an initial loss of anionic binding sites by 2 hours postinjection. At 6 hours peripheral capillary loops demonstrated only scattered, random polyethyleneimine-binding sites. Splitting of the lamina densa occurred at 24 hours with the exposure of previously undetected anionic binding sites within the lamina densa. Ultrastructurally, as early as 2 hours postnephrotoxic serum injection tissue perfused with tannic acid-glutaraldehyde showed epithelial membranes forming numerous pinocytotic vesicles. Blunting and retraction of foot processes caused displacement and stacking of slit diaphragms prior to the onset of proteinuria. Between 6 and 24 hours postinjection, slit diaphragms appeared to stretch and contract to compensate for epithelial cell retraction. Tangential sections showed neither alterations nor condensation products disrupting the isoporous substructure of the slit diaphragm 24 hours postnephrotoxic serum injection. Polymorphonuclear leukocytes were not found within capillary loops during the heterologous phase of nephrotoxic serum nephritis in MW rats. The absence of complement and polymorphonuclear leukocytes accompanying anti-GBM antibody deposition suggests that early epithelial cell injury and GBM charge alterations in MW rats are mediated by heterologous antibody via a complement-independent mechanism. The lower complement hemolytic activity in normal MW sera may explain the lack of complement involvement in renal lesions in this model of nephrotoxic serum nephritis. Loss of characteristic staining for both glomerular sialoprotein and discrete anionic sites in the GBM coincided with early epithelial cell alterations and occurred prior to the onset of measurable proteinuria.     

The effects of defibrination with ancrod in experimental allergic glomerular injury.

Quantitative studies of the effects of defibrination (with ancrod) have been undertaken in two forms of allergic glomerular damage, nephrotoxic serum nephritis and acute serum sickness in rabbits. No differences in intrarenal fixation of nephrotoxic antibody, complement activation or host antibody response were detected between defibrinated and untreated rabbits with nephrotoxic serum nephritis. Defibrination prevented intraglomerular fibrin deposition in this disease; but some glomerular damage as shown by a rise in blood urea and endothelial proliferation still occurred in defibrinated animals. No differences in immune elimination of BSA, circulating immune complex formation or intrarenal localization of immune complexes were noted in defibrinated animals with acute serum sickness. No intraglomerular fibrin deposition was detected in treated or untreated animals in this disease model. It is concluded that the protective effects of ancrod are directly related to defibrination, and not to any other modification of allergic events.     

细胞因子信号抑制因子3在小鼠肾炎进程中的表达

目的: 探索细胞因子信号抑制因子3(SOCS3)在小鼠肾炎进程中的表达变化规律和意义。方法: 采用含兔抗小鼠肾小球基底膜抗体的肾毒素血清(NTS)制备小鼠肾炎模型。在第10、15、20和25 d分别收集小鼠尿液并摘取肾脏。以蛋白尿水平、肾脏组织HE和Masson染色评价肾炎进程;采用免疫组化和Western blotting 法检测SOCS3蛋白表达变化,以及Janus激酶2(JAK2)和信号转导及转录激活因子3(STAT3)在小鼠肾炎进程中磷酸化情况。结果: 小鼠肾炎模型表现出典型的发病、进展与转归;SOCS3在肾炎进程中未出现立即随JAK2和STAT3磷酸化增多而表达增加的现象,仅在肾炎严重期(第20 d)表达增加(P<0.05),在恢复期(第25 d)表达明显增加(P<0.01)。恢复期SOCS3表达显著增加,表现出抑制JAK2和STAT3磷酸化的作用。结论: 机体自身条件下,SOCS3的表达未立即随JAK2/STAT3磷酸化增多而增加,SOCS3对免疫性肾炎的保护作用可能主要在肾炎恢复期。     

Protamine sulphate-induced proteinuria: the roles of glomerular injury and depletion of polyanion

It has been claimed that intrarenal injection of polycations results in proteinuria due to neutralization of glomerular basement membrane polyanionic charge without any glomerular morphological changes. To study the effects of polycation infusion on the renal glomerulus, the left kidney of rats was directly injected with protamine sulphate through the renal artery. Urine was collected from each kidney before and after injection, and protein excretion rates were determined. Ninety minutes after completion of the injection both kidneys were perfusion-fixed and the morphology and colloidal iron staining of the kidneys were studied by light and electron microscopy. Intrarenal injection of 0.5, 1, and 2 mg of protamine sulphate produced minimal or mild proteinuria in the majority of animals. Higher doses (5 mg) commonly resulted in decreased protein excretion associated with oliguria. Colloidal iron staining of glomerular polyanionic sites was undiminished when compared with control kidneys. Injection of protamine sulphate resulted in capillary thrombosis and severe damage to both glomerular and tubular epithelium in 6 of 16 kidneys. In the remaining kidneys, milder focal changes were apparent. Although its mechanism of action is unclear, it is apparent that protamine sulphate, even in small doses, is toxic to the cellular components of the glomerulus and tubules, thus accounting for the range of changes observed in renal function.