Lee J, Yoo K S, Kang D G, Kim S W, Choi K C
Department of Physiology, Chonnam National University Medical School, Kwangju, Korea.
Jpn J Pharmacol. 2001 Apr;85(4):391-8. doi: 10.1254/jjp.85.391.
The present study was performed to examine whether the gentamicin-induced urinary concentration defect is related to an altered regulation of aquaporin (AQP) water channels in the kidney. Male Sprague-Dawley rats were subcutaneously injected with gentamicin (20, 50 or 100 mg/kg per day) for 6 days. The protein expression of AQP1-3 channels and the catalytic activity of adenylyl cyclase were determined in the kidney. Gentamicin treatment resulted in renal failure associated with decreased tubular free water reabsorption and increased urinary flow rate. The expression of AQP2 proteins was significantly decreased in the kidney, in which the cortex was most susceptible, followed by the outer medulla and inner medulla in order. Gentamicin treatment also decreased the shuttling of AQP2, as evidenced by a decrease of its expression in the membrane fraction in proportion to that in the cytoplasmic fraction. The protein expression of AQP1 as well as that of AQP3 was also decreased in the cortex by treatment with the highest dose of gentamicin. The cAMP generation in response to arginine vasopressin or sodium fluoride was decreased by gentamicin, while that to forskolin was not significantly altered. These findings suggest that the primary impairment in the pathway leading to the generation of cAMP lies at the level of G proteins, resulting in a decreased expression of cAMP-mediated AQP channels. The gentamicin-induced urinary concentration defect may in part be accounted for by a reduced abundance of AQP water channels in the kidney.
本研究旨在探讨庆大霉素诱导的尿浓缩功能缺陷是否与肾脏中水通道蛋白（AQP）水通道调节的改变有关。将雄性Sprague-Dawley大鼠皮下注射庆大霉素（每天20、50或100mg/kg），持续6天。测定肾脏中AQP1 - 3通道的蛋白表达和腺苷酸环化酶的催化活性。庆大霉素治疗导致肾衰竭，伴有肾小管自由水重吸收减少和尿流率增加。肾脏中AQP2蛋白的表达显著降低，其中皮质最敏感，其次依次为外髓质和内髓质。庆大霉素治疗还减少了AQP2的穿梭，这表现为其在膜部分的表达与细胞质部分的表达相比有所减少。用最高剂量的庆大霉素处理后，皮质中AQP1以及AQP3的蛋白表达也降低。庆大霉素使精氨酸加压素或氟化钠刺激后的cAMP生成减少，而对福斯高林刺激后的cAMP生成无显著影响。这些发现表明，导致cAMP生成的信号通路的主要损伤位于G蛋白水平，导致cAMP介导的AQP通道表达减少。庆大霉素诱导的尿浓缩功能缺陷可能部分是由于肾脏中AQP水通道丰度降低所致。
