Chen S, Olsen K, Grigsby C, Gardner D G
Diabetes Center, University of California at San Francisco, San Francisco, California 94143-0540, USA.
Kidney Int. 2007 Aug;72(3):300-6. doi: 10.1038/sj.ki.5002274. Epub 2007 Apr 18.
Many clinical and animal studies suggest that vitamin D and its metabolites have beneficial effects in the cardiovascular and renal systems. Using immunologic and enzymatic assays, vitamin D receptor and 25 hydroxyvitamin D3 1alpha-hydroxylase activity were found in inner medullary collecting duct (IMCD) cells suggesting an autocrine/paracrine role in this nephron segment. In this study, we examined the ability of 1,25 dihydroxyvitamin D3 (1,25(OH)(2)D3) to regulate the expression of the vasculoprotective natriuretic peptide receptor-A gene in these cells in culture. Treatment of the cells with 1,25(OH)(2)D3 caused a doubling of natriuretic peptide-dependent cyclic guanosine monophosphate production and a significant increase in natriuretic peptide receptor-A protein expression. This was accompanied by significant increases in receptor mRNA levels and gene-promoter activity. Mutation of a vitamin D response element, positioned upstream from the gene start site, resulted in a complete loss of 1,25(OH)(2)D3-dependent induction but not the induction by hypertonic stimuli. Introduction of small interfering RNA directed against the vitamin D receptor into the IMCD cells resulted in decreased natriuretic peptide receptor-A gene promoter activity and protein. The increase in this receptor expression may account for some of the reported beneficial effect of 1,25(OH)(2)D3 on the cardiovascular system and kidney.
许多临床和动物研究表明，维生素D及其代谢产物对心血管系统和肾脏系统具有有益作用。通过免疫和酶学检测，在内髓集合管（IMCD）细胞中发现了维生素D受体和25羟维生素D3 1α-羟化酶活性，提示其在该肾单位节段中具有自分泌/旁分泌作用。在本研究中，我们检测了1,25-二羟维生素D3（1,25(OH)₂D3）对培养的这些细胞中血管保护型利钠肽受体-A基因表达的调节能力。用1,25(OH)₂D3处理细胞导致利钠肽依赖性环磷酸鸟苷生成增加一倍，利钠肽受体-A蛋白表达显著增加。这伴随着受体mRNA水平和基因启动子活性的显著增加。位于基因起始位点上游的维生素D反应元件发生突变，导致1,25(OH)₂D3依赖性诱导完全丧失，但高渗刺激诱导不受影响。将针对维生素D受体的小干扰RNA导入IMCD细胞导致利钠肽受体-A基因启动子活性和蛋白降低。该受体表达的增加可能解释了1,25(OH)₂D3对心血管系统和肾脏的一些有益作用。
