Torres V E, Bengal R J, Litwiller R D, Wilson D M
Division of Nephrology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
J Am Soc Nephrol. 1997 Aug;8(8):1283-91. doi: 10.1681/ASN.V881283.
The administration of ammonium chloride or of sodium or potassium bicarbonate has marked effects on the development of polycystic kidney disease (PKD) in Han:SPRD rats. Because of the possibility that these effects are mediated by changes in redox metabolism, the aim of this study was to determine whether depletion of glutathione, the most abundant and important cellular thiol and scavenger of reactive oxygen species, would affect the development of PKD in this animal model. +/+ and cy/+ Han:SPRD rats were treated with: (1) L-buthionine(S,R)-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione; (2) glutathione monoethyl ester (GME), a compound that is known to increase the intracellular levels of glutathione; or (3) BSO and GME. Treatment with these drugs was started at 3 wk of age, and the animals were killed at 6 or 8 wk of age. Renal levels of oxidized glutathione were significantly higher in cy/+ than in +/+ rats, whereas no significant differences in reduced glutathione were detected. The administration of BSO caused a marked reduction in the levels of glutathione. The administration of GME caused a significant increase in the levels of glutathione at 2 h, but not at 12 h, after the administration. The increase in the renal levels of glutathione 2 h after the administration of GME was less in the rats treated with BSO than in the rats not receiving this drug, indicating that in part the increase in glutathione level was due to de novo synthesis. BSO-induced glutathione depletion was accompanied by a marked aggravation of the renal cystic disease, as reflected by kidney weights, histological scores, and plasma urea concentrations. However, the administration of GME did not lessen the cystic disease and did not reverse the effects of BSO. The transient effect of GME administration and the simultaneous increases in the levels of cysteine and oxidized glutathione, in addition to reduced glutathione, may explain the lack of protection by GME. These data support the notion that changes in redox metabolism may affect the development of PKD.
氯化铵、碳酸氢钠或碳酸氢钾的给药对Han:SPRD大鼠多囊肾病（PKD）的发展有显著影响。由于这些影响可能是由氧化还原代谢的变化介导的，本研究的目的是确定谷胱甘肽（最丰富且重要的细胞硫醇和活性氧清除剂）的消耗是否会影响该动物模型中PKD的发展。将+/+和cy/+ Han:SPRD大鼠用以下药物处理：（1）L-丁硫氨酸（S，R）-亚砜亚胺（BSO），γ-谷氨酰半胱氨酸合成酶（谷胱甘肽合成的限速酶）的特异性抑制剂；（2）谷胱甘肽单乙酯（GME），一种已知可增加细胞内谷胱甘肽水平的化合物；或（3）BSO和GME。这些药物的处理在3周龄时开始，动物在6或8周龄时处死。cy/+大鼠肾脏中氧化型谷胱甘肽水平显著高于+/+大鼠，而还原型谷胱甘肽未检测到显著差异。BSO的给药导致谷胱甘肽水平显著降低。GME的给药在给药后2小时导致谷胱甘肽水平显著升高，但在12小时时未升高。与未接受该药物的大鼠相比，用BSO处理的大鼠在给予GME后2小时肾脏中谷胱甘肽水平的升高较少，表明谷胱甘肽水平的升高部分归因于从头合成。BSO诱导的谷胱甘肽耗竭伴随着肾囊性疾病的显著加重，这通过肾脏重量、组织学评分和血浆尿素浓度得以体现。然而，GME的给药并未减轻囊性疾病，也未逆转BSO的作用。GME给药的短暂效应以及除了还原型谷胱甘肽外，半胱氨酸和氧化型谷胱甘肽水平的同时升高，可能解释了GME缺乏保护作用的原因。这些数据支持氧化还原代谢变化可能影响PKD发展的观点。
