Mahieu Stella T, Gionotti Marisa, Millen Néstor, Elías María Mónica
Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Paraje El Pozo (3000), Santa Fe, Argentina.
Arch Toxicol. 2003 Nov;77(11):605-12. doi: 10.1007/s00204-003-0496-1. Epub 2003 Aug 20.
The aim of the present work was to study the nephrotoxicity of aluminum lactate administered for 3 months (0.57 mg/100 g bodyweight aluminum, i.p., three times per week) to male Wistar rats. Renal function was studied after 6 weeks of treatment (urine was obtained from rats in metabolic cages) and at the end of the treatment using clearance techniques. Another group of rats was used as kidneys donors at the end of treatment. The renal cortex was separated and homogenized to determine glutathione (GSH) level, glutathione S-transferase (GST) activity and lipid peroxidation (LPO) level. Renal cortex slices were also used to study the p-aminohippuric acid (PAH) accumulation during steady-state conditions and the kinetics of uptake process. Clearance results, at the end of the treatment, indicated that renal functions in treated-rats were not different from those measured in control rats, although the renal concentration parameters differ when they were measured in treated rats after 24 h of food and water deprivation. Balances of water and sodium were also modified at both 1.5 and 3 months of treatment. The activity of alkaline phosphatase (AP) relative to inulin excreted in urine was significantly impaired: controls 2.2+/-0.6 IUI/mg, Al-treated 5.1+/-0.5 IU/mg, P<0.05. These data indicated that proximal tubular cells were loosing apical brush border membranes. Data obtained in cortex homogenates indicated that both GSH and GST activity were significantly decreased, and a significant increase of LPO was noted simultaneously in Al-treated rats. Renal accumulation of PAH, estimated as slice-to-medium ratio, decreased significantly in the Al-treated rats: control rats 3.06+/-0.02 ( n=12), Al-treated rats 2.26+/-0.04 ( n=12), P<0.0001. The maximal rate of uptake was also diminished in treated rats, while the apparent affinity remained unchanged. All these results indicate that aluminum accumulation in renal tissue affects cellular metabolism, promotes oxidative stress and induces alterations in renal tubular PAH transport, together with an impairment in sodium and water balance only detected under conditions of water deprivation, without other evident changes in glomerular filtration rate or other global functions measured by clearance techniques at least at this time of chronic toxicity.
本研究的目的是研究乳酸铝对雄性Wistar大鼠连续3个月（0.57毫克/100克体重铝，腹腔注射，每周3次）给药后的肾毒性。在治疗6周后（从代谢笼中的大鼠获取尿液）以及治疗结束时使用清除技术研究肾功能。另一组大鼠在治疗结束时用作肾脏供体。分离肾皮质并匀浆以测定谷胱甘肽（GSH）水平、谷胱甘肽S-转移酶（GST）活性和脂质过氧化（LPO）水平。肾皮质切片也用于研究稳态条件下对氨基马尿酸（PAH）的积累以及摄取过程的动力学。治疗结束时的清除结果表明，治疗组大鼠的肾功能与对照组大鼠测量的肾功能无差异，尽管在禁食禁水24小时后测量治疗组大鼠的肾浓度参数时有所不同。在治疗1.5个月和3个月时，水和钠的平衡也发生了改变。相对于尿中排泄的菊粉，碱性磷酸酶（AP）的活性显著受损：对照组为2.2±0.6国际单位/毫克，铝处理组为5.1±0.5国际单位/毫克，P<0.05。这些数据表明近端肾小管细胞正在丧失顶端刷状缘膜。在皮质匀浆中获得的数据表明，铝处理组大鼠的GSH和GST活性均显著降低，同时LPO显著增加。以切片与介质的比率估计，铝处理组大鼠的PAH肾积累显著降低：对照组大鼠为3.06±0.02（n=12），铝处理组大鼠为2.26±0.04（n=12），P<0.0001。治疗组大鼠的最大摄取率也降低，而表观亲和力保持不变。所有这些结果表明，肾组织中的铝积累会影响细胞代谢，促进氧化应激，并诱导肾小管PAH转运改变，同时仅在禁水条件下检测到钠和水平衡受损，至少在此时的慢性毒性研究中，肾小球滤过率或通过清除技术测量的其他整体功能没有其他明显变化。
