Dipeptidyl Peptidase IV Regulates Proliferation of Preglomerular Vascular Smooth Muscle and Mesangial Cells

The purpose of this study was to investigate the role of dipeptidyl peptidase IV in regulating the effects of 2 of its substrates, neuropeptide Y1-36 and peptide YY1-36, 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 Y1-36 and peptide YY1-36 stimulated [H-3]-thymidine incorporation (cell proliferation index), cell number, and [H-3]-proline incorporation (index of collagen synthesis); and sitagliptin (dipeptidyl peptidase IV inhibitor) significantly enhanced most of these effects. Neuropeptide Y3-36 and peptide YY3-36 (products of dipeptidyl peptidase IV) had little effect on [H-3]-thymidine incorporation, and sitagliptin did not enhance the effects of either peptide. BIBP3226 (Y-1 receptor antagonist) blocked the effects of neuropeptide Y1-36 and peptide YY1-36 on [H-3]-thymidine incorporation in the absence and presence of sitagliptin. Neuropeptide Y1-36 and peptide YY1-36 stimulated [H-3]-thymidine and [H-3]-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 YY1-36 to peptide YY3-36 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. (Hypertension. 2012; 60: 757-764.)