Eicosanoid production by isolated glomeruli of rats with unilateral ureteral obstruction

The production of PGE2 6-keto PGF1 alpha and TxB2 under basal conditions and after exposure to angiotensin II was examined in vitro in isolated glomeruli from sham-operated control rats and rats with unilateral ureteral obstruction of 24 hour duration, that were or were not pretreated with an inhibitor of the angiotensin I converting enzyme (ACE). Basal prostanoid production was greater in glomeruli from the obstructed kidney (OK) than in glomeruli from the contralateral kidney (CLK) of rats with obstruction or glomeruli from the kidneys of sham-operated rats. Glomeruli obtained from the CLK of rats with unilateral obstruction also produced more PGE2 and 6-keto PGF1 alpha than glomeruli obtained from kidneys of sham-operated rats. Administration of an ACE inhibitor to rats with unilateral obstruction in vivo returned basal prostanoid production in vitro to levels seen in glomeruli of sham-operated rats. The increase in prostanoid production in response to angiotensin II added in vitro was less in glomeruli from rats with unilateral obstruction than in glomeruli from sham-operated rats. However, the response was restored to that seen in glomeruli of sham-operated rats after blockade of angiotensin II synthesis in vivo in rats with unilateral obstruction. Blockade of angiotensin II synthesis in sham-operated rats did not affect prostanoid synthesis by their glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)     

The expression of mRNA for tumour necrosis factor-α increases in the obstructed kidney of rats soon after unilateral ureteral ligation

Summary: Cytokines, including transforming growth factor (TGF)-β1, contribute to the tubulointerstitial fibrosis of ureteral obstruction. Tumour necrosis factor (TNF)-α, a proinflammatory cytokine produced by multiple cells including macrophages and resident renal cells, has a role in inflammatory cell recruitment in glomerular injury. We measured TNF-α mRNA in the renal cortex of rats at different times after the onset of unilateral ureteral obstruction (UUO) and determined whether angiotensin II (AngII) inhibition or total body irradiation affects the mRNA levels of TNF-α. Rats were killed at 1, 2, 4, 24, 72 and 120h after UUO. Levels of TNF-α mRNA increased significantly in the obstructed kidney at 1h (X 2), 2h (X 2.7), 4h (X 3.6), 24h (X 2.7), 72h (X 1.8) and 120h (X 2.8) after ureteral ligation when compared to the contralateral kidney of the same animals or to control (normal) kidneys. Tumour necrosis factor-α mRNA increased in renal cortical tubules but not in glomeruli. Treatment with enalapril, an angiotensin-converting enzyme (ACE) inhibitor, before and after UUO decreased TNF-α mRNA levels in the obstructed kidney by about 40% at 4h after the onset of UUO, but at 120h there was no difference in TNF-α levels in the obstructed kidney of treated and untreated animals. Total body irradiation, which depletes macrophages in the obstructed kidney, did not prevent the upregulation of TNF-α mRNA expression at 4 h after UUO. Thus, TNF-α may have a role in initiating tubulointerstitial injury in the obstructed kidney. Leucocytes infiltrating the renal interstitium of the obstructed kidney do not appear to contribute to the increased mRNA expression of TNF-α. Angiotensin II may contribute, at least in part, to the early increased expression of TNF-α mRNA in the obstructed kidney.     

mRNA expression of chemokines in rat kidneys with ureteral obstruction

BACKGROUNDS: It has been demonstrated that leukocyte infiltration, mainly of macrophages and lymphocytes, into obstructed kidneys (OBK) of rats during unilateral ureteral obstruction (UUO). Chemokines (C-C subfamily) may be involved in this mechanisms. Thus, we accessed the gene expression of chemokines in renal cortex of rats with UUO. MATERIALS AND METHODS: Female SD rats were sacrificed at various time points after UUO. mRNA expression of MCP-1, RANTES and MIP-1 alpha was determined by semi-quantitative RT-PCR. RESULTS: Control kidneys (CNK) showed a weak mRNA expression of MCP-1, RANTES and MIP-1 alpha. OBKs showed an increase in MCP-1 at 2 hours of UUO and a significant increase at 4 hours of UUO as compared with CNKs or contralateral unobstructed kidneys (CLK). The mRNA levels of RANTES and MIP-1 alpha were not increased until 72 hours of UUO in CLKs or OBKs. There were slight, but significant, differences of RANTES and MIP-1 alpha expression between OBKs and CNKs at 120 hours of UUO. CONCLUSIONS: We suggest that the early increase in MCP-1 contributes to the leukocyte infiltration and that RANTES and MIP-1 alpha plays a partial role in a late increases.     

Enhanced glomerular phospholipase activity in the obstructed kidney

Previous study demonstrated that an increment of glomerular eicosanoid production may contribute to the haemodynamic changes in the obstructed kidney. To elucidate the mechanisms responsible for enhanced glomerular eicosanoid production, the present study was designed to investigate activities of related enzymes by isolated glomeruli from rat kidney with unilateral ureteral obstruction (UUO) or bilateral ureteral obstruction (BUO) for 24 hours. The activity of phospholipase A₂ (PLA₂) was determined by monitoring [¹⁴C] arachidonate release using [¹⁴C] phosphatidylcholine (PC) or [¹⁴C] phosphatidylethanolamine (PE) as a substrate. Phospholipase C (PLC) activity was assayed by measuring the release of [³H] inositol triphosphate ([³H] IP₃) from [³H] phosphatidylinositol 4,5-biphosphate ([³H] IP₂). The activity of PE-specific PLA₂ was increased in glomeruli from the kidney with BUO and the contralateral kidney of unilateral ureteral obstruction (CLK). PLC activity was significantly greater in the cytosolic fraction of glomeruli from kidneys with UUO, BUO and CLK compared to sham-operated control. The activity of PC-specific PLA₂ was not significantly increased in any group. These results indicate that the increased synthesis of eicosanoids by glomeruli from obstructed kidney may be mediated by enhanced activities of PE-specific PLA₂ and PLC. The increased activities of these phospholipases by glomeruli from CLK may contribute to a compensatory response.     

Renal response during acute unilateral ureteral obstruction in rats

The early renal response to unilateral ureteral occlusion (UUO) and its mechanism have been extensively studied in dogs but seldom discussed in the most frequently used laboratory animals, rats. The acute phase of the renal response to UUO was studied in female rats weighing 190-236 g. We recorded the ureteral pressure and changes in renal parameters throughout 120 minutes of UUO in control (US, UUO + saline, n = 10), L-arginine-treated (UA, n = 10), and right-nephrectomized rats (UO, UUO in one kidney, n = 9). Ureteral pressure increased in all three groups of rats after complete ureteral obstruction. The extent of the increase was not significantly different between US and UA rats but was significantly higher in the UO rats. In US rats, the cortical microvascular blood flow (CMVBF), measured by a laser Doppler flowmeter, declined significantly, from 321 +/- 10 perfusion units (PU) to 260 +/- 11 PU. The percentage of drop in CMVBF at 120 minutes of UUO was significantly greater in UO (25.7 +/- 3.8 %) than in US (19 +/- 2.1%) and in UA (14 +/- 2%) rats. Acute UUO reduced the glomerular filtration rate (GFR) in US and UO rats, whereas L-arginine attenuated this decrease. The excretion of nitrate/nitrite was increased after UUO. Giving N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 12 mg/kg/h) during UUO did not reduce CMVBF more severely. Western blot analysis of endothelial nitric oxide synthase expression in the renal cortex and medulla protein extracts revealed no differences between US and sham-operated rats. Acute UUO did not lead to renal hyperemia in rats. Reduction of nitric oxide during UUO might contribute to the decrease of renal circulation during UUO.     

诱导型一氧化氮合酶在单侧输尿管梗阻大鼠肾脏的表达

目的:探讨诱导型一氧化氮合酶(iNOS)在单侧输尿管梗阻(UUO)大鼠术侧肾脏的表达.方法:建立左侧输尿管梗阻模型(UUO组),设假手术组为对照.3 d后应用逆转录-聚合酶链反应(RT-PCR)检测iNOS的mRNA水平.结果:与对照组相比,UUO组大鼠肾脏出现明显病理变化,并且其iNOS mRNA表达明显增加.结论:iNOS参与UUO的发生和发展的病理过程.     

Streptococcal zymogen type B induces angiotensin II in mesangial cells and leukocytes

Previous reports have shown that angiotensin II and oxidative stress may be important features in acute poststreptococcal glomerulonephritis (APSGN) and that streptococcal erythrogenic toxin type B (ETB) and its precursor (ETBP) may have an important role in the pathogenesis of APSGN. The aim of this study was to determine the effect of ETBP on the production of angiotensin II and oxidative stress in rat mesangial cells and human mononuclear leukocytes. Mesangial cells and leukocytes were isolated from digested glomeruli and by histopaque gradient, respectively, while ETBP was isolated from nephritogenic streptococcus cultures using a cation exchange column. Angiotensin II was determined by an enzyme-linked immunosorbent assay and by cytometrics. Superoxide anion, reduced glutathione, nitrites, lipid peroxidation and catalase activity were determined by cytochemical, biochemical and enzymatic assays. Inducible nitric oxide synthase expression was determined by cytometrics. An increased production of angiotensin II was observed in ETBP-treated mesangial cell and leukocyte cultures. The ETBP induced an elevated production of superoxide anions and nitrites in mesangial cells and superoxide anions in leukocytes, while this streptococcal protein decreased the expression of inducible nitric oxide synthase in leukocytes. The ETBP was capable of inducing an increased production of angiotensin II and increased oxidative stress, both of which may be important mediators of inflammatory events in the renal tissue and during APSGN.     

Role of leukocyte adhesion molecules in monocyte/ macrophage infiltration in weanling rats with unilateral ureteral obstruction.

BACKGROUND: Unilateral ureteral obstruction (UUO) of rats is a well-established model for studying obstructive nephropathy. Meanwhile, pathophysiology of pediatric obstructive nephropathy is not well understood. In this report, we studied monocyte/macrophage infiltration and expression of intercellular adhesion molecule 1 (ICAM-1) and macrophage antigen 1 (Mac-1) in weanling rats with UUO. METHODS: Three-week-old male Sprague-Dawley rats underwent left unilateral ureteral ligation. Both obstructed kidneys (OBK) and contralateral kidneys (CLK) were harvested at 3, 6, 12, 24, 72 and 120 h after surgery. Monocyte/macrophage infiltration and expression of ICAM-1 and Mac-1 were evaluated immunohistochemically, and results were compared with those of sham-operated control rats (SOK). RESULTS: Monocyte/macrophage infiltration was observed in the interstitium and perivascular region in the cortex of OBK within 6 h. The CLK and SOK showed slight monocyte/macrophage infiltration. Expression of ICAM-1 was markedly observed in the periarterial and peritubular interstitium and in renal cortical peritubular capillaries 12 h after obstruction. In CLK and SOK, ICAM-1 was slightly expressed in the endothelium of microvessels and parietal linings of Bowman's capsule. Expression of Mac-1 was detected mainly in cells infiltrating the perivascular interstitium in OBK. In CLK and SOK, few Mac-1-positive cells were observed. CONCLUSIONS: Adhesion molecules, ICAM-1 and Mac-1, are expected to recruit monocyte/macrophage infiltration into OBK of weanling rats with UUO.     

Apoptosis of circulating lymphocyte in rats with unilateral ureteral obstruction: role of angiotensin II

BACKGROUND: Unilateral ureteral obstruction (UUO) could induce increased renal angiotensin II (ANG II), which enhances apoptosis of renal tubular cells and renal tissue loss. Systemic ANG II is also increased in UUO. There are no data available about whether UUO can induce apoptosis of circulating lymphocytes or not. METHODS: UUO or sham-operated male Wistar rats (n = 8 in each group) were fed a drinking solution containing water, angiotensin II receptor type 1 antagonist (ARA; losartan, 500 mg/L) or angiotensin-converting enzyme inhibitor (ACEI; enalapril: 200 mg/L) for 1 day or 7 days. Blood samples were collected and circulating lymphocyte cells were separated. The apoptotic cells were detected by in situ terminal deoxynucleotidyl transferase (TdT assay)-mediated digoxigenin/antidigoxigenin conjugated fluorescein method and counted under a fluorescence microscope. The apoptotic index was calculated. RESULTS: UUO caused marked increases in the apoptotic index of circulating lymphocytes in UUO rats at both 1 day and 7 days when compared with the respective sham groups (P < 0.001). Neither ARA nor ACEI treatment had an effect on the apoptotic index values in the UUO rats at 1 day. In the UUO rats at 7 days, the apoptosis of circulating lymphocytes was markedly decreased from 29.2 +/- 2.7% to 11.9 +/- 2.7% (P < 0.01) in the ARA-treated rats and to 7.6 +/- 2.7% (P < 0.001) in the ACEI-treated rats. CONCLUSION: UUO, via stimulation of ANG II, could promptly enhance apoptosis of circulating lymphocytes. The apoptosis persisted throughout the 7 days of the study. Prolonged UUO would impair lymphocyte cell immunity and the host defense mechanism. Continuous treatment with either ARA or ACEI could abrogate ANG II-stimulated circulating lymphocyte apoptosis.     

Angiotensin II inhibits interleukin-1 beta-induced nitric oxide production in cultured rat mesangial cells

BACKGROUND: Macrophage-type nitric oxide synthase (NOS-II) is expressed in glomerular mesangial cells in response to inflammatory cytokines. Nitric oxide (NO) has antithrombotic and cytostatic activities in glomerular diseases. Recent studies have suggested that several vasoactive substances and growth factors modulate NO production in a tissue-specific manner. The aim of this study was to examine whether angiotensin II and transforming growth factor-beta (TGF-beta) modulate cytokine-stimulated NO production and NOS-II gene expression in rat glomerular mesangial cells. METHODS: Cultured rat mesangial cells were incubated with interleukin-1 beta (IL-1 beta) for 24 hours. The effects of angiotensin II and TGF-beta on stimulated nitrite accumulation and NOS-II mRNA levels were determined. RESULTS: Angiotensin II and TGF-beta significantly decreased IL-1 beta-stimulated nitrite accumulation. The angiotensin type 1 receptor antagonist CV11974 prevented angiotensin II-mediated inhibition of NO production. TGF-beta-neutralizing antibody reversed the effect of TGF-beta without affecting angiotensin II-mediated inhibition of NO production. TGF-beta markedly decreased steady-state levels of NOS-II mRNA and the half-life of the message, whereas angiotensin II did not alter these parameters. CONCLUSIONS: These results suggest that in mesangial cells, angiotensin II and TGF-beta participate in the inhibitory regulation of cytokine-induced NO production. TGF-beta inhibits NO production by decreasing NOS-II mRNA levels, whereas angiotensin II may regulate NO production at the levels after NOS-II gene expression. An autocrine action of TGF-beta induced by angiotensin II is unlikely to contribute to angiotensin II-mediated inhibition of NO production.     

H+-ATPase activity on unilateral ureteral obstruction: interaction of endogenous nitric oxide and angiotensin II

BACKGROUND: A number of cytokines, vasoactive compounds, chemoattractant molecules, and growth factors are up-regulated in obstruction. Following the onset of ureteral obstruction, angiotensin II production is rapidly stimulated. Cytokine-induced expression of inducible nitric oxide synthase (iNOS) has been reported in primary cultures of inner medullary collecting duct (IMCD) cells. We found that the defective urinary acidification in unilateral ureteral obstruction (UUO) includes an intensive decrease in bafilomycin-sensitive H+-ATPase activity in microdissected IMCD segments. METHODS: To investigate the interaction between endogenous nitric oxide and angiotensin II on H+-ATPase activity, we used microdissected IMCD segments of unilaterally obstructed, contralateral, and control kidneys to measure the bafilomycin-sensitive ATPase activity and nitric oxide synthase (NOS) activity. The generated NO was also evaluated. RESULTS: Preincubation of obstructed IMCD segments in the presence of a competitive inhibitor of NOS, NG-nitro-L-arginine methyl ester (L-NAME) 1 mmol/L, and in the presence of a specific inhibitor of calcium/calmodulin-independent NOS (iNOS), aminoguanidine 1 mmol/L, each for 60 minutes, significantly increased bafilomycin-sensitive H+-ATPase. A greater increase on iNOS activity (fmol [3H] citrulline/min/microg protein) and a lesser increase in calcium/calmodulin-dependent NOS activity (cNOS) were observed in the obstructed renal medulla. This inhibitory effect of obstruction was abolished when IMCDs were incubated with 10-5 to 10-8 mol/L losartan. Decreasing doses of the angiotensin II type 1 (AT1) receptor inhibitor caused an increase in bafilomycin-sensitive H+-ATPase, with a maximum increase at 10-8 mol/L losartan. A decrease on iNOS activity was demonstrated in the obstructed renal medulla incubated with losartan in concentrations of 10-5 to 10-8 mol/L, the same losartan concentrations that showed recovery of vacuolar H+-ATPase activity. Similarly, a decrease on the generation of NO after incubation with losartan 10-5 to 10-8 mol/L was shown. CONCLUSION: From these results, we suggest that endogenous NO increased by iNOS is involved in the inhibition of H+-ATPase activity in obstructed IMCD segments. The recovery of H+-ATPase activity in IMCD of obstructed kidneys induced by losartan may be related to a decrease of inducible NOS activity.     

Salutary role for angiotensin in partial urinary tract obstruction

BACKGROUND: In the neonatal period, angiotensin II (Ang II) is up-regulated and induces a timely development of the renal pelvis and ureteral peristalsis, thereby protecting the kidney from hydronephrosis. We tested the possibility that in adulthood, Ang II may act salutarily on the kidney structure during partial urinary tract obstruction by inducing adaptive changes in the peristaltic machinery. METHODS: Adult male Sprague-Dawley rats were subjected to partial unilateral ureteral obstruction (UUO) and divided into two groups, that is, those treated with (group L, N = 21) and those without (group C, N = 21) an angiotensin type 1 (AT1) receptor antagonist (losartan). Control animals were sham operated (N = 10). Rats were sacrificed either at day 7 or day 14. RESULTS: The degree of hydronephrosis determined morphometrically was significantly more severe in group L than group C at both day 7 and day 14, indicating that Ang II inhibition accentuated hydronephrosis. The measurement of upstream pressure within the partially ligated ureter in vivo revealed that losartan significantly attenuates the frequency of ureteral peristaltic activities. In in vitro studies using ureteral strips harvested from normal adult Sprague-Dawley rats (N = 10), Ang II (10(-8) mol/L) was shown to augment contraction, which was completely inhibited by losartan (10(-6) mol/L). CONCLUSIONS: Ang II has a salutary effect of protecting kidneys from hydronephrosis during partial ureteral obstruction through its ability to augment ureteral peristalsis.     

Induction of p27KIP1 after unilateral ureteral obstruction is independent of angiotensin II.

BACKGROUND: Unilateral ureteral obstruction (UUO) is characterized by proliferation of tubular and interstitial cells, and infiltration of the renal parenchyma with macrophages/monocytes. These alterations lead ultimately to tubulointerstitial fibrosis and tubular atrophy. Some of these changes are caused by an activated renin-angiotensin system (RAS). We have previously demonstrated that angiotensin II induces the expression of the cell cycle inhibitor p27KIP1 in cultured tubular cells. The current study tested the hypothesis that interference with the RAS may modulate renal expression of p27KIP1 after UUO. METHODS: The ureter of the left kidney of Sprague-Dawley rats was ligated. Sham-operated animals served as controls. Rats were randomized in four groups and received one of the following: no therapy, enalapril, losartan, or triple therapy (hydralazine, reserpine, hydrochlorothiazide). Kidneys were removed and cortical protein lysates were prepared for the detection of p27KIP1 by Western blotting. Immunohistochemistry was performed for p27KIP1, PCNA, ED-1, and alpha-smooth muscle actin. Apoptosis was quantified by TUNEL-staining. RESULTS: p27KIP1 expression as detected by Western blotting reached a maximum 10 days after UUO. Tubular and interstitial cells contributed to this increase in p27KIP1 expression whereas the number of glomerular p27KIP1 positive cell did not change. p27KIP1-positive cells were macrophages/monocytes (positive ED-1 staining) or had the characteristics of myofibroblasts (positive alpha-smooth muscle actin staining). Tubular and interstitial proliferation [proliferating cell nuclear antigen (PCNA)-positive staining] and apoptosis [terminal deoxy transferase uridine triphosphate nick end labeling (TUNEL) staining] also was increased after UUO. However, individual cells stained either positive for p27KIP1 or PCNA, but not both. Although enalapril and losartan reduced the number of macrophages/monocytes and attenuated the degree of tubular and interstitial apoptosis, these drugs did not influence p27KIP1 expression. There was no change in the number of p27KIP1-positive cells in the contralateral kidney undergoing hypertrophy. CONCLUSION: Induction of p27KIP1 in this model represents an endogenous response to likely limit proliferation that is independent of angiotensin II. Since there was no close correlation between apoptosis and p27KIP1 expression, it may be that the overall number of p27KIP1 expressing cells sets a general restriction point for apoptosis rather than defines an individual level of cell fate.     

Enalapril accelerates remodeling of the renal interstitium after release of unilateral ureteral obstruction in rats

Complete ureteral obstruction in rats rapidly leads to renal interstitial expansion and fibrosis and this process is ameliorated by concomitant angiotensin converting enzyme inhibition (ACEI). However, models of intervention initiated after unilateral ureteral obstruction (UUO) release may be more analogous to human obstructive renal disease where treatment could more reasonably follow the discovery of obstructive uropathy as compared to models where treatment is initiated at the time of experimentally induced obstruction. We studied interstitial changes in rats before and after release of UUO and examined the effect of ACEI with 200mg/L of enalapril (E) in the drinking water on these changes. Rats were sacrificed after 10 (n=10) and 20 (n=10) days (D) of UUO or 10D after release of 10D of UUO (n=18). Eleven rats received E for 10D after UUO release. Cortical interstitial volume fraction [Vv(I/C)] measured by point counting was increased at 10D (0.32 +/- 0.05) and 20D (0.41 +/- 0.05) of UUO compared to contralateral and sham-operated kidneys (both 0.05 +/- 0.01, ANOVA, p <0.001). Vv(I/C) 10D after release from 10D of UUO (0.26 +/- 0.04) was lower than that of 10D of UUO (p<0.05) and much lower than those with 20D of UUO (p<0.001). However, rats treated with E from the time of UUO release had lower Vv(I/C) (0.21 +/- 0.07) than UUO released E untreated rats (p<0.05). Release of UUO initiates regression of interstitial expansion in rats. ACEI with enalapril significantly accelerates reversal of interstitial expansion after UUO release. This could have important implications for treatment of obstructive nephropathy in humans.     

α-Tocopherol modulates lipoprotein cytotoxicity in obstructive nephropathy

Oxidative stress in unilateral ureteral obstruction (UUO) contributes to the development of glomerular and tubulointerstitial lesions. The present study investigated whether oxidized low-density lipoprotein (oLDL) contributes to the pathogenesis of kidney injury in UUO, and whether α-tocopherol modulates such cytotoxicity and promotes repair. Male Sprague-Dawley rats weighing 100–125 g were assigned to three groups of 6 animals each: (1) sham, regular chow; (2) UUO, regular chow; and (3) UUO, α-tocopherol supplementation. We found a significant increase in the level of oxidative stress in the UUO group as measured by malondialdehyde (MDA) content in both plasma and kidneys. The LDL isolated from this group was cytotoxic to rat mesangial cells. The level of oxidation and cytotoxicity was significantly reduced when animals were treated with α-tocopherol. Plasma cholesterol concentration, kidney MDA, and transforming growth factor β1 mRNA expression were all significantly increased in the UUO animals, and partially reduced in α-tocopherol-treated animals. Our data suggest that oxidative modification of LDL is associated with the renal injury in UUO. Taken together, our data support the concept that α-tocopherol can modulate LDL oxidation and its cytotoxic effects on rat mesangial cells in vitro. Received: 23 July 1999 / Revised: 1 November 1999 / Accepted: 1 November 1999     

A functional immature model of chronic partial ureteral obstruction

BACKGROUND: The most common nonlethal congenital anomaly of the urinary tract is ureteral obstruction without dysplasia. Although rarely progressive, the morbidity associated with metabolic and surgical management is considerable. Our study was designed to measure local and systemic pathophysiologic mechanisms in an immature model of chronic partial unilateral ureteral obstruction (UUO) after completion of glomerulogenesis. METHODS: A partial UUO was created by the method of "psoas wrap" in young male weanling rats. Control animals were sham operated. Three groups were divided as follows: sham (N= 15), UUO (N= 18), and UUO + angiotensin-converting enzyme (ACE) (N= 16) inhibitor, enalapril. Renal glomerular and tubular functions were determined by creatinine and uric acid clearances. Diuresis was assessed by urine volume, osmolality, and fractional solute excretions from samples above and below the obstruction. Proteinuria was determined by the urine protein/creatinine ratio (Up/c). RESULTS: Proteinuria was attenuated in UUO + ACE-treated animals. The hyperuricemia of the immature UUO animals was avoided by an increase in the clearance of uric acid in the UUO + ACE-treated group. Fractional solute excretions suggested a diversion of diuresis to the contralateral unobstructed kidney. CONCLUSION: Angiotensin blockade during chronic UUO in young rats affords protection by attenuating proteinuria, promoting uricosuria, and diverting solute diuresis. These data suggest a complex interaction of local and systemic mechanisms unique to the maturing kidney.     

雌激素对单侧输尿管梗阻大鼠肾间质纤维化的保护作用

目的探讨雌激素对单侧输尿管梗阻（UUO）大鼠肾间质纤维化的作用。方法雌性SD大鼠30只，随机分为4组：Ⅰ组对照组；Ⅱ组生理雌激素组；Ⅲ组低雌激素组；Ⅳ组高雌激素组。UUO术后21d处死各组大鼠，光镜观察梗阻肾组织病理变化，并分别用免疫组化和RT-PCR方法检测各组肾组织α-平滑肌肌动蛋白（α-SMA）和金属蛋白酶1组织抑制剂（TIMP-1）的表达。结果低雌激素组间质纤维化病变最明显，高雌激素组病变显著减轻（P〈0．01）。与生理雌激素组相比，低雌激素组α—SMA和TIMP-1蛋白和基因的表达增加（P〈0．05）；高雌激素组上述物质表达则减少（P〈0．05）。结论雌激素可能通过抑制α-SMA和TIMP-1的表达进而减少细胞外基质的沉积而发挥肾保护作用。     

缺氧诱导因子-1α在肾间质纤维化中的表达及意义

目的：探讨缺氧诱导因子-1α（HIF-1α）致肾间质纤维化的作用。方法：60只雄性SD大鼠随机分为假手术组（SOR）和单侧输尿管梗阻（UUO）模型组。术后第3天,第7天,第14天各处死大鼠10只,肾组织行HE染色并观察病理变化。采用免疫组织化学和荧光定量逆转录聚合酶链反应（Q-RT-PCR）法检测肾脏组织中HIF-1α、CTGF、TGF-β1蛋白和mRNA表达。结果：与假手术组相比,模型组大鼠肾脏病理损害进行性加重;HIF-1α、CTGF、TGF-β1蛋白表达随梗阻时间的延长逐渐增加;与假手术组相比HIF-lα、CTGF、TGF-β1mRNA表达明显增加（P〈0.05）;相关分析显示,模型组第3天HIF-lαmRNA表达与CTGFmRNA,TGF-β1mRNA表达分别呈正相关（r=0.748,0.659,P〈0.05）,模型组第7天组HIF-1αmRNA分别和CTGFmRNA、TGF-β1mRNA呈正相关（分别为r=0.663,0.645,P〈0.05）,模型组第14天组HIF-1αmRNA分别和CTGFmRNA、TGF-β1mRNA呈正相关（分别为r=0.515,0.752,P〈0.05）。结论：HIF-1α可能通过调节CTGF、TGF-β1的表达参与了肾间质纤维化发生和发展的过程。