Role of cAMP-phosphodiesterase isozymes in pathogenesis of murine nephrogenic diabetes insipidus.
Role of cAMP-phosphodiesterase isozymes in pathogenesis of murine nephrogenic diabetes insipidus.
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DOI：
10.1152/ajprenal.1991.261.2.f345
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发表时间：
1991-08
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影响因子：
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通讯作者：
S. Homma;S. Gapstur;A. Coffey;H. Valtin;T. P. Dousa
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作者：
S. Homma;S. Gapstur;A. Coffey;H. Valtin;T. P. Dousa
为了验证以下假设，即通过环3 '，5'-核苷酸磷酸二酯酶（PDE）快速的环磷酸腺苷（cAMP）催化是遗传性肾性尿崩症（NDI）小鼠对血管加压素（VP）无反应性的原因，我们研究了集合管[内髓（IMCD），皮质（CCD）和外髓（OMCD）导管]显微解剖对照小鼠和NDI小鼠。与正常对照组相比，NDI小鼠的IMCD（+109%）中cAMP-PDE的活性显著升高，而OMCD（+41%）和CCD（+27%）的活性则较低。与对照组相比，NDI小鼠IMCD中的cAMP PDE对PDE同工酶特异性抑制剂咯利普兰和西洛酰胺的抑制更敏感，但对3-异丁基-1-甲基黄嘌呤的抑制不敏感。NDI小鼠完整IMCD和CCD中的cAMP水平在10（-6）M VP的反应中完全没有增加。与咯利普兰单独孵育，但不与单独的西洛酰胺，恢复VP依赖性cAMP的积累在IMCD的NDI小鼠中发现在对照组小鼠的水平;此外，西洛酰胺进一步增强咯利普兰的效果。在NDI小鼠的CCD中也观察到VP依赖性cAMP系统的类似（但数量较少）异常，包括PDE抑制剂的影响。然而，VP刺激的腺苷酸环化酶活性测定透化IMCD没有不同的NDI和对照小鼠。这些结果表明，异常高活性的低Km cAMP-PDE同工酶解释了NDI小鼠集合管的失败，以增加cAMP水平在VP的响应。（250字处删节）
To test the hypothesis that rapid adenosine 3',5'-cyclic monophosphate (cAMP) catabolism via cyclic 3',5'-nucleotide phosphodiesterase (PDE) is a cause of the unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI), we investigated properties of PDEs and other aspects of the VP-dependent cAMP-signaling system in segments of collecting ducts [inner medullary (IMCD), cortical (CCD), and outer medullary (OMCD) ducts] microdissected from control mice and mice with NDI. The activity of cAMP-PDE, but not of cGMP-PDE, was markedly higher in IMCD (+109%), and to a lesser degree in OMCD (+41%) and CCD (+27%), of NDI mice than in normal controls. The cAMP-PDE in IMCD of NDI mice was more sensitive to inhibition by the PDE isozyme-specific inhibitors rolipram and cilostamide, but not by 3-isobutyl-1-methylxanthine, than was the cAMP-PDE in controls. Levels of cAMP in intact IMCD and CCD from NDI mice completely failed to increase in response to 10(-6) M VP. Incubation with rolipram alone, but not with cilostamide alone, restored VP-dependent cAMP accumulation in IMCD of NDI mice to the levels found in control mice; addition of cilostamide further enhanced the effect of rolipram. Analogous (but quantitatively lesser) anomalies of the VP-dependent cAMP system, including the effects of PDE inhibitors, were observed also in CCD of NDI mice. However, the activity of VP-stimulated adenylate cyclase assayed in permeabilized IMCD did not differ in NDI and control mice. These results indicate that anomalously high activities of low-Km cAMP-PDE isozymes account for the failure of collecting ducts of NDI mice to increase cAMP levels in response in VP.(ABSTRACT TRUNCATED AT 250 WORDS)