心钠素表达细胞移植降低高血压大鼠的血压和增加其尿量

Transplantation of atrial natriuretic peptide-expressing fibroblasts reduces blood pressure and increases urine volume in spontaneously hypertensive rats

摘要:

为探讨心钠素基因转移治疗高血压和慢性心肾功能衰竭等慢性疾病的潜力，首先利用逆转录病毒载体获得可表达和分泌人心钠素的遗传工程细胞，然后将这种细胞植于自发性高血压大鼠SHR的皮下。结果发现，人心钠素遗传工程细胞的移植可使动物血浆中的心钠素浓度在移植后第7天时明显升高。在整个实验期间，虽然实验组动物的血压会随个体发育而逐渐升高，但在实验开始后的42 d内却始终明显低于空载体组，其中第14天血压的差异高达33 mm Hg。在实验开始后的第14天和第21天，实验组动物的尿量也明显增加。以上结果说明，人心钠素遗传工程细胞的皮下移植可明显抑制SHR大鼠血压的上升趋势和改善其泌尿功能，提示该方法具有治疗高血压和慢性心肾功能衰竭等慢性疾病的潜力。

Abstract:

To investigate the potential of gene therapy for the treatment of chronic diseases such as hypertension, chronic heart failure, and chronic renal failure, we established the neonatal rat fibroblast line engineered to secrete the mutant human atrial natriuretic peptide (mhANP), and then transplanted the cell line into young spontaneously hypertensive rats (SHR) subcutaneously. We found that a single transplantation of the cell line caused an obvious rise in the concentration of mhANP in serum 7 d after transplantation ((135 ± 8) vs (106 ± 7) pg/mL, P < 0.01). The animals’ blood pressure in test group was always remarkably lower than that of empty vector group within 42 d after transplantation, even though the blood pressure in all groups was constantly increasing in the process of ontogeny ((175 ± 10) mm Hg vs (189 ± 12) mm Hg, P < 0.05). A maximal blood pressure reduction of 33 mm Hg ((157 ± 9) mm Hg vs (124 ± 112) mm Hg, P < 0.01) was observed 14 d post cell transplantation. There was a marked increase in urine volume in test group from second week after treatment beginning ((5.9 ± 0.7) mL/6 h vs (4.3 ± 0.8) mL/6 h, P < 0.01) and the effect lasted 14 d ((6.1 ± 1.1) mL/6 h vs (4.0 ± 0.8) mL/6 h, P < 0.01), however the statistical difference in concentration of K+ and Na+ in serum and urine was not observed. The results suggested that subcutaneous implantation of fibroblasts-expressing mhANP significantly reduced blood pressure in young SHR during the period of ontogeny and efficiently improved their renal function and the somatic gene transfer of mhANP may have potential value in the treatment of human chronic diseases such as hypertension, chronic heart failure, and chronic renal failure.