LYSOSOMAL IRON ACCUMULATION AND TUBULAR DAMAGE IN RAT PUROMYCIN NEPHROSIS AND AGEING

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11–12 days rats treated with puromycin (10 mg/100g, i.v.i.) had greater proteinuria (211.6 ± 35.7 mg/day, mean ± s.e.m.) and urinary iron excretion (15.4 ± 2.2 μg/day) than salinetreated controls (14.5 ± 1.4 mg/day and 1.1 ± 0.2 μg/day, respectively, both P<0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 ± 64.5 vs 11.9 ± 8.6 mg%, P<0.001), and proximal tubular cell damage assessed semi-quantitively (1.17 ± 0.10 vs 0.62 ± 0.10, P<0.001) were higher and creatinine clearance (0.15 ± 0.01 vs 0.29 ± 0.02 mL/min perg kidney weight, P<0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.     

保肾口服液影响IgA肾病小鼠T细胞增殖及分泌IL-2的实验研究

观察保肾口服液对IgA肾病小鼠T细胞^3H-TdR掺入及其分泌IL-2水平的影响，结果表明低、中、高3种浓度的保肾口服液均能显著促进IgA肾病小鼠的自发性和ConA刺激的T细胞^3H-TdR掺入，促进T细胞合成，分泌IL-2，提前给药作用相同。提示保肾口服液有显著增强IgA肾病小鼠细胞免疫功能的作用。     

Cyclosporin A (CsA) modulates the glomerular production of inflammatory mediators and proteoglycans in experimental nephrosis.

Nephrosis is characterized by glomerular epithelial cell injury and a decrease in the glomerular basement membrane (GBM) proteoglycan content. Although CsA is a useful treatment for a group of patients with this disease, its mechanism of action is unclear. We have previously shown that in experimental nephrosis there is an increase in the glomerular production of tumour necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF). Here we have studied the effect of CsA on kidney generation of TNF-alpha and PAF in puromycin aminonucleoside (PAN) nephrosis as well as on the synthesis of proteoglycans by cultured glomerular epithelial cells. Rats receiving CsA had, on day 8 of PAN injection, a significant reduction in proteinuria, blood cholesterol levels and in interstitial mononuclear cells. A diminution in glomerular production and urinary excretion of TNF-alpha and PAF was also noted. In in vitro studies, at 24 h of incubation PAF and TNF-alpha induced in glomerular epithelial cells a significant decrease in proteoglycan synthesis. Neither PAF nor TNF-alpha had any significant effect on glomerular epithelial cell proliferation. CsA alone induced a dose-response increase in proteoglycan synthesis and a slight decrease in cell proliferation. CsA also reversed the inhibitory effect of PAF and TNF-alpha on proteoglycan synthesis. However, CsA did not alter the pattern of proteoglycan production, remaining around 50% chondroitinase ABC-, 15% heparitinase-sensitive. Our results indicate that PAF and TNF-alpha could be implicated in the pathogenesis of nephrosis through the inhibition of proteoglycan synthesis by glomerular epithelial cells. The beneficial effect of CsA in nephrosis may be due to the recovery of the GBM charge selectivity caused by the normalization of glomerular PAF and TNF-alpha synthesis and the increase in proteoglycan synthesis by glomerular epithelial cells.     

Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis.     

Electron-autoradiographic study of RNA synthesis in epithelial cells of the renal tubules of albino rats poisoned with mercuric chloride

Department of Biology, Grodno Medical Institute. Department of Pathological Anatomy, A. V. Vishnevskii Institute of Surgery, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR D. S. Sarkisow.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 3, pp. 357–360, March, 1989.     

老年糖尿病肾病中药治疗前后血脂、过氧化物歧化酶的变化

目的研究益肾活血中药对老年临床糖尿病肾病（ＤＮ）的疗效和机制。方法６８例老年临床糖尿病肾病患者随 机分为治疗组（３４例,服降糖药加益肾活血中药）与对照组（３４例,仅服降糖药）。测定治疗前后患者血脂、过氧化物 歧化酶（ＳＯＤ）及血清过氧化脂质（ＬＰＯ）含量及 ２４ ｈ尿蛋白定量的变化,并分别与 ３０名健康人组作比较。结果老 年临床糖尿病患者 ＳＯＤ明显低于健康人组（Ｐ＜０．０５）,而血脂、ＬＰＯ及 ２４ ｈ尿蛋白定量均明显高于健康人组（Ｐ＜０．０１）。 治疗 ４周后治疗组 ＳＯＤ水平明显升高（Ｐ＜０．０５）,血脂、ＬＰＯ及 ２４ ｈ尿蛋白定量明显下降,与对照组相比有显著性差 异（Ｐ＜０．０５）。结论益肾活血中药对抗过氧化损伤、防治老年ＤＮ有临床意义。     

血管紧张素Ⅱ-1型受体拮抗剂对阿霉素肾病大鼠干预效果的实验研究

目的 探讨血管紧张素Ⅱ-1受体拮抗剂(AT1RA)缬沙坦对大鼠肾病综合征病理及相关临床指标的干预作用及可能机制。方法 采用阿霉素肾病(AN)模型，将大鼠分为阿霉素肾病组和缬沙坦及苯拉普利治疗组，检测大鼠24h尿蛋白排泄量、血肌酐、尿素氮及其他生化指标，并取肾脏进行光镜及电镜检查，放射免疫分析法测定血浆及肾组织血管紧张素Ⅱ含量，并没正常对照组。结果 缬沙坦及苯拉普利可降低阿霉素肾病大鼠的蛋白尿排泄，改善生化指标。结论 缬沙坦对阿霉素肾病大鼠的肾脏具有保护效应，减轻肾损伤，降低蛋白尿。     

Néphrotoxicité des produits de remplissage

Expansion of extracellular volume is a treatment traditionally proposed to correct abnormalities of renal perfusion and prevent ischemic injury. However, vascular filling is not at risk for tissue oxygenation and renal function. The use of synthetic colloids exposes the patient to the risk of developing lesions such as osmotic nephrosis. Hyperoncotic colloids reduce glomerular filtration pressure. The nephrotoxicity of hydroxyethyl starches is now clearly established regardless of their characteristics. Colloids have never demonstrated their superiority as plasma volume expanders, they should be abandoned in favour of crystalloid solutions.     

Osmotic nephrosis with mannitol: review article

Mannitol is commonly used to lower intracranial and intraocular pressures. Large doses/massive infusions of mannitol have been found to be associated with acute renal failure (MI-ARF), that is, osmotic nephrosis. While many researchers have reported individual experiences with this pathology, we felt that there is need of an updated comprehensive review of all reported cases with elaboration of etiology, pathogenesis, diagnosis and management plan for MI-ARF. The purpose of the present communication is to share our own experience with MI-ARF, to review the effect of mannitol on kidney function and to highlight the dynamics of MI-ARF with considerations for the cautious use of mannitol in patients with risk factors for kidney diseases.     

Protein Concentration and Hydrostatic Pressure in Subcutaneous Tissue of Rats in Hypoproteinemia

Protein concentration and hydrostatic pressure were measured in subcutaneous tissue of rats during development of aminonucleoside nephrosis. Samples of interstitial fluid for protein analysis were collected from subcutaneous tissue by a wick method, and hydrostatic pressure was measured by a modified Scholander technique. When the serum protein concentration was reduced from 6.1 to 4.8 g/100 ml, interstitial fluid protein concentration fell from 3.0 to 1.1 g/100 ml. This corresponds to a reduction of calculated oncotic pressures from 18.0 to 13.0 mm Hg and from 7.8 to 3.0 mm Hg in serum and interstitial fluid, respectively, thus leaving a nearly constant net transcapillary oncotic pressure. When serum protein concentration was further reduced to 3.8 g/100 ml, interstitial fluid protein concentration was reduced to 0.5 g/100 ml, reducing net transcapillary oncotic pressure by 2–3 mm Hg. The average hydrostatic pressure in subcutis was 1.0 mm Hg sub-atmospheric under control conditions and did not change during hypoproteinemia. The results indicate that a reduction of interstitial protein concentration is an important factor in preventing edema formation in hypoproteinemia.