Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219, USA.
Hypertension. 2012 Sep;60(3):757-64. doi: 10.1161/HYPERTENSIONAHA.112.196501. Epub 2012 Jul 16.
The purpose of this study was to investigate the role of dipeptidyl peptidase IV in regulating the effects of 2 of its substrates, neuropeptide Y(1-36) and peptide YY(1-36), on proliferation of and collagen production by preglomerular vascular smooth muscle and glomerular mesangial cells from spontaneously hypertensive and normotensive rats. In cells from hypertensive rats, neuropeptide Y(1-36) and peptide YY(1-36) stimulated [(3)H]-thymidine incorporation (cell proliferation index), cell number, and [(3)H]-proline incorporation (index of collagen synthesis); and sitagliptin (dipeptidyl peptidase IV inhibitor) significantly enhanced most of these effects. Neuropeptide Y(3-36) and peptide YY(3-36) (products of dipeptidyl peptidase IV) had little effect on [(3)H]-thymidine incorporation, and sitagliptin did not enhance the effects of either peptide. BIBP3226 (Y(1) receptor antagonist) blocked the effects of neuropeptide Y(1-36) and peptide YY(1-36) on [(3)H]-thymidine incorporation in the absence and presence of sitagliptin. Neuropeptide Y(1-36) and peptide YY(1-36) stimulated [(3)H]-thymidine and [(3)H]-proline incorporation and cell number in cells from normotensive rats; however, the effects were weak and mostly not affected by sitagliptin. Real-time PCR and Western blotting showed similar dipeptidyl peptidase IV mRNA and protein levels in cells from hypertensive versus normotensive rats, with greater levels in smooth muscle versus mesangial cells. Both cell types converted peptide YY(1-36) to peptide YY(3-36) in a concentration-dependent manner that was attenuated by sitagliptin, and dipeptidyl peptidase IV activity was greater in smooth muscle versus mesangial cells. In conclusion, dipeptidyl peptidase IV inhibitors might entail a risk of renal dysfunction because of abnormal proliferation of cells in the preglomerular microcirculation and glomeruli.
本研究旨在探讨二肽基肽酶 IV 在调节其两种底物神经肽 Y(1-36)和肽 YY(1-36)对自发性高血压和正常血压大鼠肾小球前血管平滑肌和肾小球系膜细胞增殖和胶原产生的影响中的作用。在高血压大鼠的细胞中，神经肽 Y(1-36)和肽 YY(1-36)刺激[(3)H]-胸苷掺入(细胞增殖指数)、细胞数量和[(3)H]-脯氨酸掺入(胶原合成指数)；西他列汀(二肽基肽酶 IV 抑制剂)显著增强了这些作用中的大多数。神经肽 Y(3-36)和肽 YY(3-36)(二肽基肽酶 IV 的产物)对[(3)H]-胸苷掺入几乎没有影响，西他列汀也没有增强这两种肽的作用。BIBP3226(Y1 受体拮抗剂)阻断了神经肽 Y(1-36)和肽 YY(1-36)对[(3)H]-胸苷掺入的作用，而西他列汀不存在或存在时均阻断了该作用。神经肽 Y(1-36)和肽 YY(1-36)刺激正常血压大鼠的细胞[(3)H]-胸苷和[(3)H]-脯氨酸掺入和细胞数量；然而，这些作用较弱，且大多不受西他列汀的影响。实时 PCR 和 Western blot 显示高血压大鼠与正常血压大鼠的细胞中二肽基肽酶 IV mRNA 和蛋白水平相似，平滑肌细胞中的水平高于系膜细胞。两种细胞类型均以浓度依赖性方式将肽 YY(1-36)转化为肽 YY(3-36)，该转化被西他列汀减弱，且平滑肌细胞中的二肽基肽酶 IV 活性高于系膜细胞。总之，二肽基肽酶 IV 抑制剂可能会因肾小球前微循环和肾小球中的细胞异常增殖而导致肾功能障碍的风险。
