Abstract
Dipeptidyl peptidase IV inhibitors are a new class of antidiabetic drugs. It is urgent, therefore, to fully understand the pharmacology of these inhibitors. Although dipeptidyl peptidase IV metabolizes at least 24 endogenous substrates, the pharmacological consequences of inhibiting the metabolism of most of these substrates is unknown. Our previous results show that Y1 receptors, but not Y2 receptors, enhance renovascular responses to angiotensin II in kidneys from genetically susceptible animals (spontaneously hypertensive rats). Dipeptidyl peptidase IV converts peptide YY1–36 (circulating hormone) to peptide YY3–36, and peptide YY1–36 is a Y1-receptor agonist, whereas peptide YY3–36 is a selective Y2-receptor agonist. Therefore, it is conceivable that inhibition of dipeptidyl peptidase IV in genetically susceptible kidneys may increase the ability of peptide YY1–36 to potentiate angiotensin II-induced renal vasoconstriction. Here we demonstrate that in kidneys from spontaneously hypertensive rats 1) peptide YY1–36 potentiates renovascular responses to angiotensin II, whereas peptide YY3–36 has little effect, 2) 3-N-[(2S,3S)-2-amino-3-methylpentanoyl]-1,3-thiazolidine (P32/98) (dipeptidyl peptidase IV inhibitor) augments the ability of peptide YY1–36 to enhance renovascular responses to angiotensin II, 3) dipeptidyl peptidase IV is expressed in preglomerular microvessels and glomeruli, 4) kidneys metabolize arterial PYY1–36 to PYY3–36 via a mechanism blocked by P32/98, and 5) preglomerular microvessels and glomeruli convert peptide YY1–36 to peptide YY3–36, and this conversion is inhibited by P32/98. We conclude that dipeptidyl peptidase IV is expressed in the renal microcirculation and inhibition of this ecto-enzyme causes arterial PYY1–36 to more effectively enhance angiotensin II-induced renal vasoconstriction in genetically susceptible kidneys.
Footnotes
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This work was supported by National Institutes of Health Grants HL69846 and DK068575.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126847.
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ABBREVIATIONS: DPP IV, dipeptidyl peptidase IV; PYY1–36, peptide YY1–36; Y1R, Y1 receptor; Ang II, angiotensin II; SHR, spontaneously hypertensive rat(s); WKY, Wistar-Kyoto rat(s); Y2R, Y2 receptor; PYY3–36, peptide YY3–36; BIBP3226, N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-d-arginine amide); P32/98, 3-N-[(2S,3S)-2-amino-3-methylpentanoyl]-1,3-thiazolidine; PBS, phosphate-buffered saline; RT, reverse transcription; PCR, polymerase chain reaction; TBST, Tris-buffered saline-Tween 20; LSD, least significant difference; UK14,304, 5-bromo-6[2-imidazoline-2-yl amino]quinoxaline; LPNPY, Leu31-Pro34-neuropeptide Y.
- Received June 6, 2007.
- Accepted August 27, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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