Different roles of two types of endothelin receptors in partial ablation-induced chronic renal failure in rats

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• 作者：Shimizu ; Toshikatsu ; Hata ; Satoshi ; Kuroda ; Takayuki ; Mihara ; Shin-ichi ; Fujimoto ; Masafumi
• 关键词：Endothelin ; Endothelin receptor ; Endothelin receptor antagonist ; Renal failure ; chronic ; Renal function ; Proteinuria ; RT-PCR (reverse transcription-polymerase chain reaction)
• 刊名：European Journal of Pharmacology
• 出版年：1999
• 出版时间：September 17, 1999
• 年：1999
• 卷：381
• 期：1
• 页码：39-49
• 全文大小：337 K

文摘

Recent work has drawn attention to endothelin as a likely contributor to renal pathogenesis. To elucidate the mechanism of progressive renal disease, we investigated the mRNA expression of endothelin and endothelin receptors, and the effect of endothelin ET_A, and/or ET_B receptor antagonists on disease progression in the remnant kidney model. Proteinuria progressively increased in rats subjected to 5/6 nephrectomy (Nx) after 8 weeks (from 25±3 to 221±28 μg min⁻¹ kg⁻¹). Creatinine clearance (Ccr) after renal ablation gradually decreased by 8 weeks (from 5.04±0.42 to 2.68±0.26 ml min⁻¹ kg⁻¹). Together with maximal proteinuria and decreased renal function, there was an increase in cortical mRNA expression of prepro endothelin-1 and endothelin ET_A receptor expression, but a decrease in endothelin ET_B receptor expression and in urinary excretion of endothelin-1. Administration (1–3 mg/day) of S-0139, (+)-disodium 27-[(E)-3-[2-[(E)-3-carboxylatoacryloylamino]-5-hydroxyphenyl]acrylayloxy]-3-oxoolean-12-en-28-oate, an endothelin ET_A receptor-specific antagonist, had a beneficial effect on the evolution of the disease, preventing the appearance of intense proteinuria (113±11) and decreased Ccr (3.97±0.33). High blood pressure was observed in rats with 5/6 Nx and was decreased by S-0139 administration. To examine whether treatment modalities that decrease endothelin ET_B receptor signaling have a deleterious effect on the kidney remnant, the effect of 97-618, an endothelin ET_B receptor-specific antagonist, 4-tert-butyl-N-[5-(2-methoxyphenoxy)-6-(4-oxobutoxy)pyromidine-4-yl]benzenesulfonamide, was also examined on the action of S-0139. Concomitant administration of S-0139 and 97-618 reversed the beneficial effect of S-0139 alone in the remnant kidney on proteinuria and renal functional impairment. These findings indicate that endothelin participates in the pathogenesis of proteinuria and glomerular injury and that an endothelin ET_A receptor-specific antagonist could be useful in the treatment of some forms of human nephritis. The loss of endothelin ET_B receptor seems to be important in the progression of renal disease.