Kook H, Kim S W, Kang S Y, Kim S Z, Kim J H, Choi K C, Lee J, Cho K W, Baik Y H
Research Institute of Medical Sciences, Chonnam University Medical School, Kwangju 501-746, Republic of Korea.
Pharmacol Res. 2000 Nov;42(5):435-41. doi: 10.1006/phrs.2000.0699.
In order to elucidate the involvement of the atrial natriuretic peptide (ANP) and its receptor (natriuretic peptide receptor; NPR) system in cyclosporine-induced nephrotoxicity, we investigated the cyclosporine A (CsA)-induced changes in characteristics of the NPR/guanylyl cyclase system in the glomerulus and inner medulla of the rat kidney. CsA was administered intramuscularly to rats for 2 weeks (CsA group). Particulate guanylyl cyclase activity was measured in glomerular and inner medullary membranes. For receptor characteristics, quantitative in vitro receptor autoradiography was performed. The guanylyl cyclase activity in the glomerulus from the CsA group was attenuated compared with that from the control. However, the activity in the inner medulla was not affected by CsA treatment. Direct application of CsA to normal glomerular membrane completely abolished the ANP-induced guanylyl cyclase activation. Binding studies, using(125)I-ANP, revealed that B(max)was decreased in the CsA group, while K(d)was not affected in the glomerulus. However, in the inner medulla, neither B(max)nor K(d)was affected by CsA treatment. CsA did not displace the(125)I-ANP bindings to NPRs in the normal rat kidney. Local tissue ANP as well as plasma ANP concentration in both groups was not significantly different. These results indicate that CsA impairs the guanylyl cyclase activity mainly in the glomerulus by the decrease in NPR population and/or by direct inhibition, suggesting that the ANP/NPR system might be involved in CsA-induced nephrotoxicity.
为了阐明心房利钠肽（ANP）及其受体（利钠肽受体；NPR）系统在环孢素诱导的肾毒性中的作用，我们研究了环孢素A（CsA）诱导的大鼠肾脏肾小球和髓质中NPR/鸟苷酸环化酶系统特性的变化。将CsA肌肉注射给大鼠2周（CsA组）。测定肾小球和髓质膜中的颗粒性鸟苷酸环化酶活性。对于受体特性，进行了定量体外受体放射自显影。与对照组相比，CsA组肾小球中的鸟苷酸环化酶活性减弱。然而，髓质中的活性不受CsA处理的影响。将CsA直接应用于正常肾小球膜完全消除ANP诱导的鸟苷酸环化酶激活。使用（125）I-ANP的结合研究表明，CsA组的B（max）降低，而肾小球中的K（d）不受影响。然而，在髓质中，B（max）和K（d）均不受CsA处理的影响。CsA不会取代正常大鼠肾脏中（125）I-ANP与NPRs的结合。两组的局部组织ANP以及血浆ANP浓度无显著差异。这些结果表明，CsA主要通过NPR数量减少和/或直接抑制损害肾小球中的鸟苷酸环化酶活性，提示ANP/NPR系统可能参与CsA诱导的肾毒性。
