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 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.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219, USA. edj@pitt.edu
Edwin K
EK
Jackson
Stanton J
SJ
Kochanek
Delbert G
DG
Gillespie
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000494:pharmacology; D010446:Peptide Fragments; D019894:Peptide YY / Q000378:metabolism / Q000494:pharmacology; D011392:Proline / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000068900:Sitagliptin Phosphate; D013936:Thymidine / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
C092926:BIBP 3226; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009478:Neuropeptide Y; D010446:Peptide Fragments; D011719:Pyrazines; D014230:Triazoles; D019894:Peptide YY; C061785:peptide YY (3-36); D052216:Glucagon-Like Peptide 1; D001120:Arginine; D011392:Proline; D018819:Dipeptidyl Peptidase 4; C514549:peptide YY (1-36); D000068900:Sitagliptin Phosphate; D013936:Thymidine