Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats
Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats
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DOI：
10.1111/j.1523-1755.2004.00913.x
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发表时间：
2004-10-01
影响因子：
19.6
通讯作者：
Ishibashi, S
中科院分区：
文献类型：
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作者：
Fujisawa, G;Okada, K;Ishibashi, S
背景资料。肾小球和肾小管间质损伤会导致慢性肾功能损害，因此逆转这种损伤可能会改善肾功能和提高存活率。本研究调查了盐皮质激素受体拮抗剂螺内酯是否以及如何改善链脲佐菌素诱导的糖尿病大鼠的早期肾损伤。链脲佐菌素(65 mg/kg，单次腹腔注射)组大鼠为糖尿病大鼠，赋形剂组大鼠为对照组。链脲佐菌素组大鼠皮下注射螺内酯(50 mg/kg/d)，连续3周。采用天狼星红染色和ED-1巨噬细胞标志物、纤溶酶原激活物抑制物-1(PAI-1)、转化生长因子-β1的免疫组织化学方法，比较3组大鼠肾脏纤维化和肾肥厚的差异。链脲佐菌素给药三周后，大鼠肾小球、肾小管间质和血管周围区域的胶原沉积增加，螺内酯治疗可完全减轻这一现象。单用链脲佐菌素大鼠肾小球和肾小管间质ED-1阳性细胞、PAI-1表达和转化生长因子-β1表达增加，而螺内酯治疗可抑制其表达。3组间最大肾小球面积和近端肾小管面积差异无统计学意义。单独给予链脲佐菌素的大鼠近端小管壁/腔比增加，但不受螺内酯治疗的影响。链脲佐菌素诱导的肾脏纤维化、PAI-1的表达、转化生长因子-β1的表达和巨噬细胞的浸润都是通过盐皮质激素受体发生的，而螺内酯可能通过抑制巨噬细胞的浸润、PAI-1的表达和转化生长因子-β1的表达而减轻糖尿病早期糖尿病损伤中的肾纤维化。
Background. Glomerular and tubulointerstitial injury leads to chronic impairment of renal function, and thus, reversal of the injury may improve renal function and survival. The present study investigated whether and how mineralocorticoid receptor antagonist spironolactone ameliorates early renal injury in streptozotocin-induced diabetic rats.Methods. Streptozotocin (65 mg/kg, single intraperitoneal injection)-or vehicle-administered rats were used as diabetic or control rats, respectively. The streptozotocin-administered rats were treated with spironolactone (50 mg/kg/day sc) for 3 weeks. Among the 3 groups of rats, we compared renal fibrosis and renal hypertrophy, using picro-sirius red staining and immunohistochemistry of ED-1 macrophage marker, plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor (TGF)-beta1.Results. Three weeks after administration of streptozotocin, rats exhibited increased collagen deposition in glomerular, tubulointerstitial, and perivascular areas in the kidney, which was completely attenuated by spironolactone treatment. In rats given streptozotocin alone, there were increases in ED-1-positive cell, PAI-1 expression, and TGF-beta1 expression in glomeruli and tubulointerstitiums, which were also suppressed by spironolactone treatment. Maximal glomerular and proximal tubular areas were not significantly different among the 3 groups. Rats given streptozotocin alone revealed an increase in proximal tubule wall-to-lumen ratio that was not influenced by treatment with spironolactone.Conclusion. Streptozotocin-induced renal fibrosis, PAI-1 expression, TGF-beta1 expression, and macrophage infiltration occur via mineralocorticoid receptor, and spironolactone ameliorates renal fibrosis presumably via the inhibition of macrophage infiltration, PAI-1 expression, and TGF-beta1 expression in streptozotocin-induced early diabetic injury.