The course of the remnant kidney model in mice.

The remnant kidney model was produced in mice by unilateral nephrectomy and partial infarction of the remaining kidney. Control mice underwent laparotomy only. The mice were studied for up to 44 weeks. No quantitative differences were noted in systolic arterial pressure, proteinuria, or histopathology between control mice and those with a remnant kidney. Glomerular enlargement occurred in the remnant kidney.     

当归注射液对大鼠残肾微血管的影响

目的 探讨当归注射液对大鼠残肾模型肾脏新生血管形成的作用。方法 选择SD雄性大鼠19只,建立5／6肾切除大鼠慢性肾衰竭模型并将其随机分为3组（假手术组6只、生理盐水对照组6只、当归治疗组7只）。12周后,采血、收集24h尿并进行肾脏病理检杳。采用免疫组化染色技术分析浸润肾组织巨噬细胞数、毛细血管密度和增生的内皮细胞数。结果 与假手术组相比,对照组肾功能下降、肾间质纤维化明显、肾小球毛细血管指数（GCI）和肾小管周毛细血管指数（PCI）均显著降低（P〈0．01）;当归治疗组GCI和PCI明显增加（P〈0．05）,肾功能恶化、肾问质纤维化程度明显改善,而且GCI和PCI与肌酐清除率（CCr）、间质纤维化程度密切相关。结论 当归注射液能促进大鼠新生血管的形成并增加毛细血管的密度,从而延缓肾问质纤维化的发生。     

肾上腺切除对5/6肾切除大鼠肾脏的保护作用

目的通过切除5／6肾切除大鼠的肾上腺,探讨醛固酮对慢性肾脏疾病发生及发展的作用。方法雄性Wister大鼠分成5组:(1)假手术组(SHAM组);(2)5／6肾切除组(SNX组); (3)SNX+双肾上腺切除组(ADX组);(4)ADX+地塞米松组(DXM组);(5)ADX+地塞米松+醛固酮组(ALDO组)。所有大鼠自由饮用生理盐水,于成模第8周测定大鼠收缩压、各项血尿指标及肾小球硬化程度。应用Western印迹和实时定量PCR检测大鼠肾皮质TGF-β1、醛固酮受体 (MR)及保护MR的酶11β-羟类固醇脱氢酶2(11β-HSD2)的mRNA表达水平。结果 SNX组大鼠表现为明显的白蛋白尿、高血压、肾小球硬化、肾皮质TGF-β1表达升高,血醛固酮水平是 SHAM组的4倍以上。与SNX组比较,ADX组大鼠血浆醛固酮水平明显下降,同时病变明显改善 [尿白蛋白(mg／24 h)19．7±2．0比31．7±1．7,P<0．01;收缩压(mmHg)173．8±4．3比210．4±4．1,P <0．01;肾小球硬化指数38．2±7．9比92．3±6．7,P<0．01;TGF-β1 3．8±0．6比10．3±1．2,P< 0．01]。ALDO组的血浆醛固酮水平为SHAM组的近2倍,与ADX组比较,以上病变又加重[尿白蛋白(mg／24 h)24．9±1．4,收缩压(mmHg)201．5±4．5,肾小球硬化指数88．1±7．2,TGF-β1 5．8± 0．6,P均<0．01]。肾脏皮质MR mRNA在SNX组的表达明显增加;在ADX组明显下降[SNX(复制数／百万GAPDH)39866．7±10579．0比SHAM 2366．7±446．3,P<0．05;比ADX 22100．0±4435．7, P<0．05]。然而,11β-HSD2 mRNA表达和MR相反,SNX组为9150．0±969．9,明显低于SHAM组 (48100．0±9315．2,P<0．05);而ADX组的表达比SNX组显著升高(30066．7±5150．2,P<0．05)。 4个实验组大鼠肾脏Ccr和肾重／体重无显著性差别。结论醛固酮参与慢性肾脏病变的进展, 其对肾小球损伤的作用除血流动力学效应外,还可能存在非血流动力学的直接致纤维化作用。     

霉酚酸酯对肾大部切除大鼠肾脏的保护作用

目的 观察霉酚酸酯在肾大部切除大鼠模型中对残肾的保护作用并探讨其可能的机制。方法 采用5/6肾大部切除模型,分别给予霉酚酸酯(MMF,15 mg·kg-1·d-1),福辛普利(25mg·kg-1·d-1)及两药合用。8周后观察大鼠24 h尿蛋白、BUN、Scr以及肾脏病理改变。并用免疫组化观察了胶原Ⅳ、纤连蛋白(FN)、增殖细胞核抗原(PCNA)和巨噬细胞趋化蛋白1(MCP-1)。用RT-PCR的方法测定了肾皮质中转化生长因子β1(TGF-β1)和组织性金属蛋白酶抑制剂1(TIMP-1)mRNA的表达。结果 两药均能减少尿蛋白,降低BUN和Scr,合用组减少最为明显。病理上,肾大部切除组可见基质增生,肾小球硬化,用药后病变减轻。其中应用MMF者可见PCNA和MCP-1明显减少。结论 在5/6肾大部切除模型中,MMF能通过抑制肾脏中的异常增殖、减少MCP-1的表达,下调TGF-β1和TIMP-1,减少细胞外基质,减少尿蛋白,从而明显减轻肾脏的损害。     

血管紧张素Ⅱ对大鼠残肾模型微血管的影响

目的 探讨大鼠残肾模型中血管紧张素Ⅱ与肾脏新生血管形成间的关系。方法 分别用缬沙坦、氨氯地平或生理盐水治疗大鼠残肾模型12周,测定24h尿蛋白排泄量、血压、BUN和Scr;评估病理切片肾小球硬化和肾小管间质损害程度;采用免疫组化染色技术,分析浸润肾组织巨噬细胞数、毛细血管密度和增生内皮细胞数。结果 缬沙坦和氨氯地平可显著减少残肾模型尿蛋白排泄量、降低血压、改善肾功能、抑制巨噬细胞浸润、减轻肾小球硬化和肾间质纤维化(P<0.05),但缬沙坦组尿蛋白显著少于氨氯地平组(P<0.05)。残肾模型肾小球毛细血管指数(GCI)和肾小管周毛细血管指数(PCI)均显著低于假手术组(P<0.01)。缬沙坦或氨氯地平治疗均显著增加肾小球和肾间质毛细血管数目(P<0.05),而缬沙坦组显著高于氨氯地平组(P<0.05)。缬沙坦或氨氯地平组肾小球和肾间质增生内皮细胞数分别高于生理盐水对照组(P<0.01),而缬沙坦组显著高于氨氯地平组(P<0.01)。结论 缬沙坦能改善大鼠残肾模型新生血管形成和增加毛细血管密度,血管紧张素Ⅱ可能通过直接抑制新生血管形成和升高血压间接加速毛细血管毁损而加重肾缺血和肾损害。     

Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model.

Increasing evidence supports a role of glomerular cell proliferation in the development of focal or diffuse glomerulosclerosis. This study investigates the chronology and sequence of cellular events that precede glomerulosclerosis in 5/6 nephrectomized rats. Within three days of renal ablation, a phenotypic switch occurred in which some mesangial cells expressed alpha-smooth muscle actin. This was followed by proliferation of mesangial cells, and to a lesser degree endothelial cells from day 5 to week 4 as detected by immunostaining for the proliferating cell nuclear antigen (PCNA). Glomerular cell proliferation was accompanied by increased immunohistochemical expression of PDGF B-chain. In situ hybridization showed no glomerular PDGF B-chain mRNA expression at the induction of proliferation (day 5), and a marked increase between week 1 and 4 in operated rats. In parallel, increased expression of PDGF receptor beta-subunit protein and mRNA was demonstrated by immunohistochemistry and Northern analysis of total glomerular RNA. The onset of glomerular cell proliferation was also associated with mild glomerular platelet accumulation (as defined by 111In-labelled platelet studies) as well as with fibrinogen deposition. Proteinuria, glomerular sclerotic changes, and leukocyte infiltration all followed cell proliferation. The glomerular leukocyte infiltrate consisted of monocytes/macrophages and increased markedly at week 10 in rats with renal ablation. Thus, our results suggest that in the remnant kidney model: 1) proliferation of intrinsic glomerular cells precedes glomerulosclerosis; 2) proliferation may be initiated by degranulating platelets and sustained by PDGF released from intrinsic glomerular cells; and 3) glomerular monocyte/macrophage infiltration occurs after the proliferation, and may possibly contribute to the development of glomerular sclerotic changes.     

Estradiol is nephroprotective in the rat remnant kidney.

BACKGROUND: Female sex hormones may influence the progression of renal diseases. We therefore evaluated the effects of estradiol on the development of glomerulosclerosis in a remnant kidney model. METHODS: Ovariectomized or intact female Wistar rats underwent 5/6 nephrectomy. Ovariectomized animals were treated with vehicle, 17beta-estradiol alone or in combination with progesterone, intact rats received vehicle only. Twenty-four weeks after renal ablation, histological as well as molecular analysis were performed. RESULTS: Vehicle-treated ovariectomized animals developed severe proteinuria and glomerulosclerosis as compared with vehicle-treated intact rats. In addition, renal mRNA levels of platelet-derived growth factor-A chain (PDGF-A) were increased. Estradiol replacement reduced proteinuria, which was paralleled by a diminished glomerular injury and reduced transforming growth factor-beta1 (TGF-beta1) and PDGF-A mRNA expression. In animals that received combined hormone treatment there were no significant differences in proteinuria, creatinine clearance, renal histopathology and growth factor mRNA levels compared with those measured in vehicle-treated ovariectomized rats. Serum cholesterol and triglyceride levels were comparable between all groups during the whole follow-up period. CONCLUSIONS: The data suggest that estrogens protect against the development of glomerulosclerosis in the rat remnant kidney model.     

The porcine remnant kidney model of chronic renal insufficiency

BACKGROUND: The purpose of the present study was to develop and characterize a porcine model of chronic renal insufficiency created by renal artery embolization. METHODS: The model was created using 42 castrated juvenile male pigs (7-8 months old) in two parts (pilot (N = 10) group, definitive (N = 26) group, and control group (N = 6). In the pilot group, the embolization procedure was optimized with respect to the size of polyvinyl acrylide (PVA) particles, coils, and amount of kidney embolized. The animals were followed serially for 4 weeks after the embolization procedure to determine the renal function and hypertensive response. In the definitive group, these results were extended to later time points and a left total nephrectomy and a right partial nephrectomy (remnant) were performed and these animals were followed for 28 to 84 days. RESULTS: The kidney function after the embolization was characterized by acute deterioration in renal function, followed by improvement, and "stable" chronic renal insufficiency with statistically significant elevation in creatinine and BUN being observed until day 42. The mean arterial blood pressure remained significantly elevated until day 7 after which it began to decrease to pre-embolization value. The remnant kidney developed fibrosis in the tublointerstitial compartment as it hypertrophied and increased its weight which remained significantly elevated after embolization. CONCLUSIONS: A reproducible remnant kidney model of chronic renal insufficiency in pigs was developed. In this model, stable renal insufficiency develops by 4 weeks that lasts until 12 weeks.     

Low protein diet mediated renoprotection in remnant kidneys: Renal autoregulatory versus hypertrophic mechanisms

BACKGROUND: The mechanism of low protein diet conferred renoprotection in the ablation model remains controversial. Blockade of glomerular hypertrophy, reduced preglomerular vasodilation, and preserved autoregulation have all been postulated. The potential differential impact of calcium channel blockers on these mechanisms and glomerulosclerosis was examined. METHODS: Rats with 5/6 renal ablation received either a 25% standard protein diet, an 8% low protein diet and a low protein diet with either verapamil or amlodipine. Renal autoregulatory and morphometric studies were performed at 3 weeks before the development of significant injury, and the assessment of glomerulosclerosis after 7 weeks of continuous blood pressure radiotelemetry in additional rats. RESULTS: The preserved renal autoregulation in low protein rats was abolished by both calcium channel blockers, with the impairment being either comparable to (low protein + verapamil) or greater than the standard protein rats (low protein + amlodipine). Neither calcium channel blocker blocked the inhibitory effects of low protein diet on renal blood flow, kidney weight, and glomerular volume. Results (mean +/- SE) for glomerular volume (microm-3x 10(-6)): low protein (N = 11), 1.6 +/- 0.1; low protein + verapamil (N = 10), 1.7 +/- 0.1; low protein + amlodipine (N = 12), 1.7 +/- 0.2; versus standard protein (N = 10), 2.2 +/- 0.1; P < 0.05. Only amlodipine, but not verapamil, reduced average systolic blood pressure (143 +/- 2 mm Hg versus low protein rats, 168 +/- 5 mm Hg, and standard rats, 170 +/- 6 mm Hg; P < 0.01). Nevertheless, the glomeruloprotection seen in low protein (N = 15) as compared to standard protein (N = 14) rats (9%+/- 3% versus 28%+/- 6% glomerulosclerosis; P < 0.01) was abolished in both low protein + verapamil (N = 14, 32%+/- 7%) and low protein + amlodipine rats (N = 16, 27%+/- 7%). CONCLUSIONS: Preservation of renal autoregulation and not inhibition of hypertrophy is the critical component in low protein diet-conferred glomeruloprotection.     

Effect of lactate on the absorption and retention of aluminum in the remnant kidney rat model

In previous investigations we found the gastrointestinal absorption of aluminum (Al) to be enhanced in uremic rats and this phenomenon could not be attributed to either calcitriol deficiency or secondary hyperparathyroidism. The purpose of this study was to examine whether carboxyl ligands such as lactate could affect the absorption of A1 in our model and, if so, whether this would impose additional alterations on the A1 absorption in uremia. Uremic rats and controls were studied with single oral loads of either A1 chloride or A1 lactate and, subsequently, urinary A1 excretion was measured for 5 days. Compared with Al chloride, administration of A1 lactate resulted in significantly higher urinary excretion rates of A1 in uremic rats (55.5 +/- 22.7 vs. 27.4 +/- 7.0 micrograms; 2.06 +/- 0.84 vs. 1.01 +/- 0.26 mumol) and in controls (23.6 +/- 8.5 vs. 11.9 +/- 4.3 micrograms; 0.87 +/- 0.31 vs. 0.44 +/- 0.16 mumol). However, with either A1 load the recovery of A1 from urine was substantially higher in uremic animals. In contrast, only in controls was there a more pronounced rise in serum A1 concentrations following ingestion of A1 lactate, whereas in uremic rats this increase had a similar magnitude following A1 chloride and A1 lactate, suggesting a larger apparent volume of distribution of the latter. Adjustment of the pH of the A1 lactate-containing solution to 7.0 or oral administration of sodium lactate together with A1 chloride yielded essentially similar results. These observations indicate that the enhanced intestinal absorption of A1 in uremia is further augmented by lactate regardless of the mixture of hydroxolactato complexes employed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of oral administration of heparan sulphate in the rat remnant kidney model

Heparins are useful for the protection of residual renal function in several nephropathies, but the anticoagulant action and the need of parenteral administration are two main drawbacks limiting their use in chronic renal failure patients. Heparan sulphate (HS) is a heparin-like mucopolysaccharide devoid of anticoagulant action and active orally. In this study, the effects of HS oral administration have been evaluated in 18 subtotally nephrectomized rats;18 untreated remnant kidney rats served as control. No mortality was observed in the HS-treated rats, whereas in the control rats the survival rate was 72.2% at 18 weeks. At the end of the study, HS-treated rats showed lower urinary protein excretion (44 +/- 22 vs. 80 +/- 54 mg/24 h, p < 0.01), lower urea plasma levels (75 +/- 34 vs. 134 +/- 105 mg/dl, p < 0.01) and higher creatinine clearance (66 +/- 15 vs. 47 +/- 21 ml/min. 10(2), p < 0.05) than control rats. Remnant kidney weight (2.3 +/- 1.1 vs. 1.3 +/- 0.2 g, p < 0.01) and heart weight (1.3 +/- 0.2 vs. 1.1 +/- 0.1 g, p < 0.05) were greater in the control than in the HS-treated rats, as well as the systemic blood pressure values (167 +/- 19 vs. 115 +/- 32 mm Hg, respectively, p < 0.001). The remnant kidney histological examination in the HS-treated rats showed a lower prevalence of glomerular sclerosis, mesangial proliferation, and a much less evident tubulointerstitial damage than in controls. The antiproliferative and anti-inflammatory actions of HS together with its protective action on the endothelium are the putative mechanisms that could account for our findings. In conclusion, the present study supports evidence of an antiproteinuric and a renoprotective effect of orally administered HS in subtotally nephrectomized rats. This is in keeping with the well-known effects exerted also by other heparins, but the effectiveness of an orally available heparin-like product in this animal model could suggest the possibility of a clinical use also in progressing chronic renal failure patients.     

Role of dietary potassium in the hyperaldosteronism and hypertension of the remnant kidney model

The remnant kidney model of progressive renal disease is marked by arterial hypertension, especially when produced by nephrectomy and partial infarction. Hyperaldosteronism sustains much of the hypertension, but the stimuli to the increased aldosterone levels are uncertain. It is hypothesized that the hyperaldosteronism attending this model stems from the combination of fixed dietary potassium load in the face of reduced filtration on the one hand, and persistent renin secretion from the scarred remnant kidney on the other. This hypothesis predicted that dietary potassium restriction would lower aldosterone and BP in this model. To test this prediction, two groups of rats with a remnant kidney were studied. Group 1 consumed 0.4 +/- 0.06 mEq (mean +/- SD) of potassium chloride daily, and group 2 ate 4.8 +/- 1.0 mEq daily. Two sham-operated groups with intact kidneys also were studied. Group 3 consumed 1.7 +/- 0.2 mEq daily and group 4 ate 15.2 +/- 1.4 mEq daily. These levels of intake were designed to provide at least as much potassium per liter of GFR in the sham groups as in the remnant kidney rats. Systolic BP (SBP), 24-h protein excretion, plasma aldosterone levels, 24-h urinary aldosterone excretion, and plasma renin activity (PRA) were determined in all groups at 2 wk. At 4 wk, after SBP and protein excretion measurements, remnant kidneys were perfusion-fixed for morphometric analysis. SBP was normal in both sham-operated groups and was not different between the groups (113 +/- 13 versus 117 +/- 2 mmHg, group 3 versus group 4). In the remnant animals, SBP at 2 wk followed potassium intake: Group 1 had a lower SBP than group 2 (140 +/- 26 versus 170 +/- 34 mmHg, P = 0.005). The same SBP pattern persisted at 4 wk (153 +/- 25 versus 197 +/- 27 mmHg, group 1 versus group 2, P = 0.0006). However, 24-h urinary protein excretion was not different between the two groups with remnant kidneys at either 2 or 4 wk. Both plasma and 24-h urinary aldosterone excretion at 2 wk followed potassium intake (120 +/- 124 versus 580 +/- 442 pg/ml for plasma aldosterone, group 1 versus group 2, P = 0.03, and 2.6 +/- 1.8 versus 23.2 +/-9.8 ng/d for urinary aldosterone, group 1 versus group 2, P = 0.0001). PRA, however, followed a reverse pattern in which dietary potassium restriction resulted in higher levels (16 +/- 6 versus 6 +/- 3 ng angiotensin I/ml per h, group 1 versus group 2, P = 0.01). A similar pattern for PRA and aldosterone excretion was also observed in the sham groups, in which lower potassium intake also resulted in a significantly higher PRA and lower aldosterone excretion. The constancy of BP in the sham groups likely reflects their lack of nephron reduction and greater sodium excretory capacity. Morphometric analysis in remnant animals revealed no significant difference between the two dietary groups in the prevalence of glomerular sclerosis, glomerular volume, or interstitial volume. It is concluded that dietary potassium is a potent determinant of hypertension in the remnant kidney model probably through the actions of aldosterone and that the high aldosterone secretion in this model is a function of the dietary potassium load. In this model, reduction in nephron number is also critical in promoting hypertension in conjunction with hyperaldosteronism.     

Vascular endothelial growth factor expression and glomerular endothelial cell loss in the remnant kidney model.

BACKGROUND: Vascular endothelial growth factor (VEGF) is constitutively expressed in the glomerulus where it may have a role in the maintenance of capillary endothelial cell integrity. The present study sought to examine changes in VEGF expression in a model of progressive renal disease and to assess the effects of angiotensin converting enzyme (ACE) inhibition. METHODS: Subtotal nephrectomized (STNx) rats were randomly assigned to receive vehicle (n=10) or the ACE inhibitor perindopril (8 mg/l drinking water) for 12 weeks duration (n=10). Sham-operated rats were used as controls (n=10). Glomerular capillary endothelial cell density was evaluated by immunostaining for the pan-endothelial cell marker RECA-1 and VEGF expression was assessed by quantitative in situ hybridization. RESULTS: In STNx rats glomerular capillary endothelial cell density was reduced to 19% that of sham rats (P<0.01) with a concomitant reduction in glomerular VEGF expression, also to 19% of sham rats (P<0.01). Perindopril treatment was associated with normalization of both capillary endothelial cell density and glomerular VEGF mRNA. CONCLUSIONS: Reduction in glomerular VEGF expression is a feature of the renal pathology that follows subtotal nephrectomy. In the context of the known functions of this growth factor, these findings suggest that diminution in VEGF may contribute to the demonstrated loss of glomerular endothelium that develops in this model of progressive renal disease.     

Class differences in the effects of calcium channel blockers in the rat remnant kidney model

BACKGROUND: Controversy persists as to the existence of class differences between calcium channel blockers (CCBs) in their ability to provide renoprotection and as to potential mechanisms involved. METHODS: Rats with 5/6 renal ablation were left untreated or received diltiazem, verapamil, or felodipine after the first week, and the relationship between continuous radiotelemetrically measured blood pressure (BP) and glomerulosclerosis (GS) was assessed at seven weeks. Additionally, the effects of these CCBs on renal autoregulation and hypertrophy were examined at three weeks after renal ablation. RESULTS: Although an excellent linear correlation was observed between the average BP levels and GS in all groups (r = 0.75 to 0.84, P < 0.01), significant protection was not achieved with any of the CCBs, but for different reasons. The antihypertensive effects of diltiazem were not sustained beyond the second week. Verapamil significantly reduced the average BP (144 +/- 4 mm Hg vs. 181 +/- 8 in untreated rats) but shifted the slope of the relationship between BP and GS (increase in percentage GS/mm Hg increase in average systolic BP) to the left (x intercept 121 vs. 144 mm Hg for untreated rats, P < 0.01) so that GS was not reduced. Felodipine also significantly reduced the average BP (144 +/- 3 mm Hg) and shifted the slope to the left (x intercept 123 mm Hg), but additionally made the slope steeper (2.3 +/- 0.5 vs. 0.82 +/- 0.2 in untreated rats). Because of these differing effects on the relationship between BP and GS, the rank order of GS for any given BP elevation was as follows: felodipine > verapamil > diltiazem = untreated. Felodipine, but not verapamil or diltiazem, caused additional impairment of the already impaired renal autoregulation in untreated rats, thereby explaining its adverse effects on GS. By contrast, the adverse effects of verapamil on GS were attributable to the greater amplitude of BP fluctuations that was observed in the verapamil-treated rats such that for any given average BP, these rats were exposed to greater peak pressures as compared with the other groups. None of the CCBs had a significant effect on glomerular hypertrophy. CONCLUSIONS: These class differences between CCBs in their relative impact on systemic BP profiles, renal autoregulation, and glomerular pressure transmission may have clinically significant implications and may account for the variable glomeruloprotection that has been observed with these agents in both experimental models and in humans.     

Intrarenal angiotensin and bradykinin peptide levels in the remnant kidney model of renal insufficiency

BACKGROUND: The remnant kidney model of renal failure is associated with normal or suppressed plasma renin and angiotensin (Ang) II levels when hypertension is established. However, the hypertension responds to angiotensin-converting enzyme (ACE) inhibition and Ang II receptor antagonism, suggesting a role for Ang II in the hypertensive process. Bradykinin (BK) is a potent vasoactive peptide that may also participate in this model. METHODS: Ang II and BK peptides were measured in the ischemic peri-infarct portion and the intact portion of the remnant kidney at two, five, and seven weeks after surgery. Plasma Ang II, renin, angiotensinogen, and aldosterone levels were also measured. RESULTS: Ang II levels in the peri-infarct portion were higher than in the intact portion at all time points and were higher than in sham-operated kidney at two weeks. Ang II levels in the intact portion were similar to the levels in kidneys of sham-operated rats at two and five weeks and were suppressed at seven weeks. BK levels were increased in the peri-infarct portion at all time points and in the intact portion at two and five weeks. Plasma Ang II and aldosterone levels were also elevated at two weeks. CONCLUSIONS: Peri-infarct renal tissue Ang II levels and plasma Ang II and aldosterone levels increase transiently during the evolution of hypertension in the remnant kidney model. Sustained hypertension is associated with an increase in intrarenal BK levels but not with persistent increases in intrarenal or circulating Ang II levels.     

Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model

Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-beta has been consistently implicated. Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-beta-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 (x)/(/) 1.2 versus 20.5 (x)/(/) 1.3 mg/d; P < 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P < 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-beta activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-beta signaling in vivo. In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.     

Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model

Accumulation of plasma advanced oxidation protein products (AOPP) has been found in patients with chronic kidney disease. However, the biologic consequences of AOPP consumption on progression of renal disease still are unclear. For testing of the hypothesis that AOPP accelerate progression of chronic kidney disease, Sprague-Dawley rats were subjected to five-sixths nephrectomy (5/6 Nx) or to sham operation. Rats in each group were randomly assigned in three subgroups (n = 30 in each group) and treated with repeated intravenous injections of AOPP-modified rat serum albumin (RSA), unmodified RSA, or vehicle for indicated period. Compared with RSA- or vehicle-treated 5/6 Nx rats, AOPP RSA-treated 5/6 Nx rats displayed greater proteinuria, higher serum creatinine, and lower creatinine clearance. AOPP challenge resulted in more renal hypertrophy, higher macrophage influx, and greater renal fibrosis in the remnant kidney. Chronic administration of AOPP in sham-operated rats increased urinary protein excretion and renal macrophage infiltration, but histologic renal fibrosis was not observed during the study period. AOPP treatment enhanced AOPP level in renal tissue. This was associated with marked increase of thiobarbituric acid reactive substances, decrease of glutathione peroxidase activity, and upregulated expression of monocyte chemoattractant protein-1 and TGF-beta1 in renal cortex. These data indicate that AOPP might be a new and potentially important mediator of renal fibrosis in the remnant kidney. Chronic accumulation of AOPP promotes renal fibrosis probably via a redox-sensitive inflammatory pathway.     

The impact of early normalization of haematocrit by erythropoietin on renal damage in the remnant kidney model

Background: Correction of anaemia in moderate to advanced renal failure is still a matter of debate because of postulated detrimental effects of erythropoietin on the progression of renal damage. Methods: The renal effects of early normalization of haematocrit (Htc) by erythropoietin (rHuEpo) were investigated from the time of 5/6 nephrectomy up to 8 weeks post-intervention in three groups of remnant kidney model rats: untreated controls (CON), rats receiving 100 UI/kg body-wt of rHuEpo i.p. twice a week (EPO), and rats receiving rHuEpo in which periodic phlebotomies maintained Htc similar to the value of the control group (PHL). The latter group was included to evaluate the direct effects of rHuEpo on renal damage, i.e. independent from Htc correction. Results: Two weeks after renal ablation (basal), Htc decreased in CON and PHL (from 49.3±1.4% to 43.2±1.1, P<0.05 and from 49.6±1.1 to 43.3±1.5% P<0.05 respectively), while it remained consistently normal in EPO rats (78.9±1.2% to 48.8±1.5%, P<0.05 vs other groups). Thereafter Htc did not change throughout the remaining period in all groups. At the end of the study, with respect to basal, resting blood pressure increased significantly by the same extent in CON (+13±2%) and EPO rats (+15±5%), while it remained constant in PHL rats. Notably, creatinine clearance significantly decreased in CON (-53±8% vs basal) and EPO (-38±8% vs basal), while it did not change in PHL rats. Likewise the degree of proteinuria as well as renal morphologic alterations and glomerular hypertrophy/sclerosis was similar in CON and EPO rats, and was significantly more severe than in the phlebotomized group. The only difference detected between CON and EPO group was the greater mesangial hypercellularity in rHuEpo-treated rats. Conclusion: In uraemic rats, chronic treatment with rHuEpo aimed at normalization of Htc beginning the early stage of renal failure does not inevitably account for a rise in systemic blood pressure. In addition, neither erythropoietin per se nor the correction of haematocrit accelerates the progression of renal damage when blood pressure remains constant.