Rodgers G M, Fisher J W, George W J
Am J Med. 1975 Jan;58(1):31-8. doi: 10.1016/0002-9343(75)90530-6.
A regulatory role for adenosine 3',5'-monophosphate (cyclic AMP) in the production of the renal hormone rythropoietin following erythropoietic stimulation with cobaltous chloride hexahydrate is proposed. Studies in rates reveal a temporal relationship between renal cyclic AMP levels and plasma titers of erythropoietin. In addition, cobalt increases the activity of an erythropoietin-generating enzyme (renal erythropoietic factor) with maximal enzyme activity occurring after the rise in cyclic AMP levels but before the increase in erythropoietin titers. This increase in renal cyclic AMP is localized to the renal cortex. Cobalt stimulates renal cortical adenylate cyclase but has no effect on renal cyclic nucleotide phosphodiesterase. The addition of cyclic AMP (3 time 10-6 M) and a partially purified cyclic AMP-dependent protein kinase from rat kidney to an inactive preparation of renal erythropoietic factor increases the ability of renal erythropoietic factor to generate erythropoietin. Data from the polycythemic mouse assay, a bioassay used to quantitate erythropoietic activity of test substances, indicate that dibutyryl cyclic AMP is erythropoietically active with respect to its ability to increase radioactive-labelled iron (59Fe) incorporation into heme of newly formed red blood cells. Theophylline, which by itself is erythropoietically inactive, potentiated the erythropoietic effect of cobalt in polycythemic mice. These results suggest that cyclic AMP plays a significant role in the renal production of erythropoietin following cobalt administration. It is postulated that cobalt stimulates renal cortical adenyoate cyclase, thus increasing renal cyclic AMP levels. Cyclic AMP then activates a protein kinase which subsequently stimulates renal erythropoietic factor to generate erythropoietin. A similar cyclic AMP mechanism may be operative after erythropoietic stimulation by exposure to hypoxia or prostaglandin treatment.
有人提出，3',5'-环磷酸腺苷（环磷酸腺苷）在六水合氯化钴促红细胞生成刺激后对肾脏激素促红细胞生成素的产生具有调节作用。对大鼠的研究揭示了肾脏环磷酸腺苷水平与促红细胞生成素血浆滴度之间的时间关系。此外，钴可增加促红细胞生成素生成酶（肾脏促红细胞生成因子）的活性，在环磷酸腺苷水平升高后但促红细胞生成素滴度增加之前出现最大酶活性。肾脏环磷酸腺苷的这种增加局限于肾皮质。钴刺激肾皮质腺苷酸环化酶，但对肾脏环核苷酸磷酸二酯酶没有影响。将环磷酸腺苷（3×10-6M）和来自大鼠肾脏的部分纯化的环磷酸腺苷依赖性蛋白激酶添加到无活性的肾脏促红细胞生成因子制剂中，可增加肾脏促红细胞生成因子产生促红细胞生成素的能力。来自红细胞增多症小鼠试验（一种用于定量测试物质促红细胞生成活性的生物测定法）的数据表明，二丁酰环磷酸腺苷在增加放射性标记铁（59Fe）掺入新形成红细胞的血红素方面具有促红细胞生成活性。茶碱本身无促红细胞生成活性，但可增强钴对红细胞增多症小鼠的促红细胞生成作用。这些结果表明，环磷酸腺苷在钴给药后肾脏促红细胞生成素的产生中起重要作用。据推测，钴刺激肾皮质腺苷酸环化酶，从而增加肾脏环磷酸腺苷水平。然后环磷酸腺苷激活一种蛋白激酶，该蛋白激酶随后刺激肾脏促红细胞生成因子产生促红细胞生成素。在暴露于缺氧或前列腺素治疗引起的促红细胞生成刺激后，类似的环磷酸腺苷机制可能起作用。
