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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Departments of Pharmacology (E.K.J.) and Medicine (E.K.J., W.L., Z.M.) and Center for Clinical Pharmacology (E.K.J., M.Z., W.L., Z.M.), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
Received June 6, 2007; accepted August 27, 2007.
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Abstract |
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; Bailey, 2005; Demuth et al., 2005). Drugs in this class, such as sitagliptin (Januvia), which has recently been approved by the Food and Drug Administration, afford significant and sustained reductions in hemoglobin A1c with a low risk of hypoglycemia and little effect on body weight (Barnett, 2006). DPP IV inhibitors are efficacious both as monotherapy and in combination with other antidiabetic drugs and are effective when administered orally once daily. These characteristics of DPP IV inhibitors, along with the emerging uncertainty regarding the safety of thiazolidinediones (Nissen and Wolski, 2007), make it highly likely that DPP IV inhibitors will be extensively used in the epidemic of type 2 diabetes. Thus, there is some urgency to fully understand the pharmacology of this new class of drugs.
Because DPP IV metabolizes incretin hormones, such as gastric inhibitor peptide and glucagon-like peptide-1, DPP IV inhibitors raise circulating levels of incretin hormones and thereby exert antidiabetic actions by increasing insulin release. However, incretin hormones are not the only endogenous substrates for DPP IV. In fact, there are at least 24 peptide substrates for DPP IV (Gorrell, 2005), and inhibition of DPP IV has the potential to influence levels of a broad array of biologically active peptides. One peptide of particular importance is peptide YY1–36 (PYY1–36).
PYY1–36 is a member of the pancreatic polypeptide-fold family of peptides that is released from endocrine L-cells in the small bowel, colon, and rectum, producing physiologically active levels of PYY1–36 in plasma. Thus, a fatty meal increases plasma PYY1–36 levels by as much as 500 to 1000% above basal circulating levels (Pappas et al., 1986; Armstrong et al., 1991; Fu-Cheng et al., 1997; Anini et al., 1999; MacIntosh et al., 1999; Teixeira et al., 2001; Korner et al., 2005), and this circulating PYY1–36 would be delivered promptly to all organs, including the renal microcirculation via the bloodstream (humoral input to kidney microcirculation).
Because PYY1–36 is a potent agonist of Y1 receptors (Y1Rs) (Michel et al., 1998; Berglund et al., 2003), PYY1–36 release from the gut has the potential to activate Y1Rs in the renal microcirculation, and this could have consequences in the appropriate genetic background. In this regard, our previously published results indicate that activation of renovascular Y1Rs markedly enhances renovascular responses to physiological levels of angiotensin II (Ang II) in kidneys of spontaneously hypertensive rats (SHR). In sharp contrast, in kidneys from normotensive Wistar-Kyoto rats (WKY), activation of renovascular Y1Rs does not enhance renovascular responses to Ang II (Dubinion et al., 2006b). Our studies also show that, unlike Y1Rs, renovascular Y2 receptors (Y2Rs) exert little effect on Ang II-induced renovascular responses in kidneys of either SHR or WKY (Dubinion et al., 2006b).
The facts that PYY1–36 is a potent Y1R agonist and that Y1R agonism potentiates Ang II-induced renal vasoconstriction in genetically susceptible kidneys have implications for the pharmacology of DPP IV inhibitors. DPP IV converts PYY1–36 to PYY3–36 (McIntosh et al., 2005) by cleaving two amino acids from the N terminus of PYY1–36. Whereas PYY1–36 is a potent Y1R agonist, PYY3–36 is inactive at Y1Rs but is a potent and selective Y2R agonist (Michel et al., 1998; Berglund et al., 2003). These facts suggest the hypothesis that inhibition of DPP IV in the kidneys may enhance the ability of arterial PYY1–36 to potentiate renovascular responses to Ang II in genetically susceptible kidneys by preventing the metabolism of PYY1–36 (a Y1R agonist) to the less active PYY3–36 (a Y2R agonist). The purpose of this investigation was to test this hypothesis.
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Materials and Methods |
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).
Vasoconstriction Experiments in Isolated, Perfused Kidneys. SHR or WKY were anesthetized with Inactin (90 mg/kg i.p.; Sigma-Aldrich, St. Louis, MO), and the left kidney was isolated and perfused with Tyrode's solution using a Hugo Sachs Elektronik-Harvard Apparatus GmbH (March-Hugstetten, Germany) kidney perfusion system as described previously (Gao et al., 2003). In brief, all branches of the left renal artery and vein were ligated. A polyethylene-50 cannula was placed into the left renal artery, and a polyethylene-90 cannula was placed into the left renal vein. The left kidney was removed, attached to the perfusion system, and allowed to stabilize for 1 h before the experimental protocol. Kidneys were perfused (single pass mode) at a constant flow (5 ml/min), and perfusion pressure was monitored with a pressure transducer. The change in perfusion pressure induced by Ang II was measured in the absence and presence of PYY1–36, PYY3–36, BIBP3226, and/or P32/98h. PYY1–36, PYY3–36, Ang II, and BIBP3226 were obtained from Sigma-Aldrich, and P32/98 was purchased from Tocris Cookson Inc. (Ellisville, MO).
Immunocytochemistry for DPP IV. SHR were anesthetized with Inactin, and the left kidney was removed. The kidney was cut longitudinally, placed in phosphate-buffered formalin (10%) overnight at 4°C, and then transferred into phosphate-buffered saline (PBS) containing 30% sucrose. After incubation at 4°C for 2 days, the kidney was embedded in a plastic mold and frozen overnight at –80°C. The kidney block was placed in a cryostat chamber (–25°C) and cut into 10-µm sections, which were stored at –20°C. For immunocytochemistry, the section was dried at room temperature for 30 min and then washed three times with PBS. The section was blocked with 5% goat serum in PBS with Tween 20 for 1 h and then washed three times with PBS. Next, CD26 antibody (1:50; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was added to the section to cover all the tissue, and the section was incubated at 4°C overnight and then gently washed three times with PBS. Finally, the section was incubated for 2 h at room temperature with a donkey anti-goat IgG-fluorescein isothiocyanate-conjugated secondary antibody (1:200) and then washed three times with PBS followed by a single wash in deionized water. Slides were examined using fluorescence microscopy.
Isolation of Renal Preglomerular Microvessels and Glomeruli. Preglomerular microvessels and glomeruli were isolated by an improved method recently developed and published by us (Jackson et al., 2004). In brief, SHR were anesthetized with Inactin, and the kidneys were flushed via the renal arteries with oxygenated L15 medium (Sigma-Aldrich) at room temperature. A 1% suspension of iron oxide (Sigma-Aldrich) in oxygenated L15 medium (room temperature) was flushed into the kidneys via the renal arteries. The kidneys were harvested, placed in oxygenated, ice-cold L15 medium, and dissected by removing the renal medulla and interlobar arteries. The cortex was sliced into small pieces, suspended in oxygenated, ice-cold L15 medium and dispersed by pushing the cortical material through a series of increasingly small needle hubs (16, 18, 21, and then 23 gauge). The dispersed cortical material was suspended in ice-cold, oxygenated L15 medium, and a magnet was applied to the tube to retrieve the iron oxide-laden microvessels and glomeruli while the unwanted material was decanted. The glomeruli were separated from the microvessels by filtering the suspension through a 149-µm nylon mesh. The microvessels were retrieved from the nylon mesh, whereas the glomeruli were recovered from the filtrate. Microvessels and glomeruli were washed three times with ice-cold oxygenated L15 medium using magnetic separation.
RT-PCR for Expression of DPP IV mRNA. Total RNA was purified from isolated tissues by TRIzol Reagent (Invitrogen, Carlsbad, CA). RNA (1 µg) was treated with DNase I at 37°C for 1 h to remove any remaining DNA. The treated RNA was extracted with phenol-chloroform and precipitated with isopropanol. RT-PCR on the DNA-free RNA was carried out using the TITANIUM One-Step RT-PCR Kit (Clontech, Mountain View, CA). The forward and reverse primers were 5'-TCCAAACGGCACTTTTCTAGCT-3' and 5'-TTCCGTCGGAGGTGAAGTG-3', respectively, and the final PCR product was 454 base pairs. Each PCR cycle (40 cycles total) consisted of denaturing at 94°C for 30 s, annealing at 58°C for 30 s, and extension at 68°C for 34 s. RT-PCR products were separated on a 1.2% agarose gel, and gels were stained with ethidium bromide.
Western Blotting for Expression of DPP IV Protein. The isolated tissues were frozen with liquid nitrogen and ground to a powder. The powder was suspended in lysis buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 5 mM EDTA, 5 mM EGTA, and 1% Triton X-100) with 1x proteinase inhibitor (Sigma-Aldrich). The suspended tissue was homogenized for 20 s and centrifuged at 3000 rpm for 10 min. The supernatant was decanted, and the pellet was resuspended in lysis buffer for 2 h at room temperature and 4 h at 4°C. The suspension was centrifuged at 14,000 rpm for 2 min, and the supernatant containing the soluble proteins was stored at –80°C. The soluble proteins were quantified with the BCA Protein Assay (Pierce Chemical, Rockford, IL), and equal amounts of total protein were loaded onto NuPAGE 4 to 12% Bis-Tris gels (Invitrogen) and subjected to electrophoresis. Proteins were transferred to polyvinylidene difluoride membranes at a constant 36 V for 2 h. The membranes were first incubated for 1 h at room temperature with 5% fat-free milk in 1x TBST and then incubated overnight at 4°C with the first antibody, which was anti-rat CD26 monoclonal antibody (1:200; Pierce Chemical). The membrane was washed three times with 1x TBST for 5 min, the second antibody (1:1000; horseradish peroxidase-conjugated donkey anti-rat IgG) was added with 5% fat-free milk in 1x TBST, and the mixture was incubated at room temperature for 2 h. The membranes were washed 3 times with 1x TBST for 5 min at room temperature, and the final wash was 1x PBS for 5 min at room temperature to remove the detergent. The membranes were then incubated for 5 min in SuperSignal West Dura Substrate Working Solution (Pierce Chemical) and exposed to X-ray film.
Assay for PYY3–36. PYY3–36 levels in the medium were measured using a radioimmunoassay kit (catalog no. PYY-67HK; Millipore, Billerica, MA) that recognizes only PYY3–36 and does not cross-react with PYY1–36. This assay has a sensitivity of 20 pg/ml, an accuracy of 94.5% and intra-assay and interassay coefficients of variation of 7 to 15% and 6 to 11%, respectively.
Statistical Analysis. Data were analyzed by one-factor or repeated measures two-factor analysis of variance, as appropriate. Fisher's least significant difference (LSD) test was used for post hoc analyses if a significant analysis of variance was obtained. The criterion of significance was P < 0.05. All data are presented as means ± S.E.M.
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; Pederson et al., 1998), PYY1–36 (1 nM), P32/98 + PYY1–36, or P32/98 + PYY1–36 + BIPB3226. None of these treatments affected basal perfusion pressure. After the 10-min pretreatment with the aforementioned agents and while infusion of these agents continued, a second concentration-response relationship to Ang II was generated using the same protocol as that used for the first concentration-response relationship. As shown in Fig. 2, the concentration-response relationship for Ang II versus change in perfusion pressure was not affected by time or vehicle or by P32/98. PYY1–36 at the lower concentration of 1 nM also did not affect the concentration-response relationship for Ang II (Fig. 3). However, in the presence of P32/98, this low concentration of PYY1–36 shifted the concentration-response relationship for Ang II to the left approximately 2-fold, and this shift was highly statistically significant (P = 0.0010). The P value was 0.0010 despite the small difference in the two concentration-response relationships because we used a repeated-measures two-factor analysis of variance to analyze the shifts within each individual kidney. This procedure is analogous to a paired t test, and, like a paired t test, this approach provides a very significant P value when all the experiments go in the same direction with similar magnitudes, as was the case in these experiments. BIBP3226 abolished the ability of PYY1–36 + P32/98 to enhance renovascular responses to Ang II, and, in fact, there was a small but significant reduction in Ang II-mediated responses in the presence of PYY1–36 + P32/98 + BIBP3226 (Fig. 4).
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Because the changes induced by PYY1–36 + P32/98 in the second protocol were modest, we decided to perform yet another protocol using a 10-fold higher concentration of P32/98 and a very low, physiological concentration of Ang II. In this third protocol, we examined the effects of increasing concentrations of PYY1–36 (0.1, 0.3, 1, and 3 nM) in the absence and presence of P32/98 (50 µM) on vasoconstrictor responses to a very low, physiologically relevant concentration of Ang II. These experiments were conducted in both SHR and WKY kidneys. In SHR, the basal response to 100 pM Ang II was 4 ± 1 mm Hg (n = 14), and this basal response was not affected by P32/98. As shown in Fig. 5, top, in SHR PYY1–36 concentration-dependently enhanced the vasoconstrictor response to Ang II. However, the vasoconstrictor response was enhanced by PYY1–36 more so in the P32/98-treated SHR kidneys compared with the nontreated SHR kidneys (P = 0.0133). For example, 3 nM PYY1–36 potentiated Ang II-induced vasoconstriction by 3.7-fold in control kidneys, yet enhanced Ang II-induced vasoconstriction by 11.4-fold in P32/98-treated kidneys. In WKY, 100 pM Ang II did not yield a detectable response; therefore, we used 300 pM Ang II, which provided a basal response of 5 ± 1 mm Hg (n = 10) that was not affected by P32/98. In WKY kidneys (Fig. 5, bottom), PYY1–36 did not enhance responses to Ang II either in the absence or presence of P32/98.
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Immunocytochemistry of the SHR kidney revealed expression of dipeptidyl peptidase IV in glomeruli (Fig. 6), and RT-PCR using primers specific for dipeptidyl peptidase IV resulted in an appropriately sized amplicon detected in the renal cortex, renal medulla, glomeruli, and preglomerular microvessels (Fig. 6). Western blotting revealed a predominant band at 220 kDa in both glomeruli and preglomerular microvessels (Fig. 6), consistent with the fact that in vivo active DPP IV exists as a dimer of two monomers of the 110-kDa glycoprotein (McIntosh et al., 2005).
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Discussion |
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), it is conceivable, therefore, that inhibition of renovascular DPP IV has the potential to increase the ability of PYY1–36 to potentiate renovascular responses to Ang II in genetically susceptible kidneys by preventing the conversion of PYY1–36 (a Y1R agonist) into PYY3–36 (a Y2R agonist).
The hypothesis that inhibition of DPP IV could augment the renovascular impact of PYY1–36 in genetically susceptible kidneys is supported by our observations that inhibition of DPP IV with P32/98 increases the ability of PYY1–36 to enhance renovascular responses to Ang II in genetically susceptible kidneys. Most likely renovascular DPP IV inactivates PYY1–36 so that low concentrations cannot enhance the renovascular effects of Ang II; however, when DPP IV is inhibited, this inactivation is impaired and so even low concentrations of PYY1–36 potentiate renovascular responses to Ang II.
Importantly, immunocytochemistry indicates that SHR glomeruli express DPP IV and RT-PCR demonstrates a strong expression of DPP IV mRNA in both SHR glomeruli and renal microvessels. In addition, Western blotting reveals a 220-kDa protein in SHR glomeruli and renal microvessels that corresponds in size to the dimeric form of DPP IV (McIntosh et al., 2005). These findings lend biochemical evidence in support of the hypothesis that inhibition of renovascular or glomerular DPP IV could significantly alter the ability of PYY1–36 to potentiate Ang II-induced renal vasoconstriction. However, whether the expression of DPP IV is associated with vascular smooth muscle cells, vascular or glomerular endothelial cells, vascular fibroblasts, mesangial cells, glomerular podocytes, or resident immune cells is not clear from the present results.
If renovascular or glomerular DPP IV operates to inactive PYY1–36, then PYY1–36 in the arterial supply to the kidney should be readily metabolized to PYY3–36 as the PYY1–36 transverses the renal circulation. The assay used in the present study detects PYY3–36, yet has no cross-reactivity with PYY1–36. Using this assay system, our results demonstrate that administering PYY1–36 to the isolated, perfused kidney is as effective as administering PYY3–36 with regard to increasing PYY3–36 levels in the renal venous effluent. These results are consistent with robust conversion of PYY1–36 to PYY3–36 as PYY1–36 courses through the renal vasculature. Importantly, the ability of PYY1–36 to increase renal venous levels of PYY3–36 is impaired in kidneys pretreated with a DPP IV inhibitor, a finding consistent with the hypothesis that the conversion of PYY1–36 to PYY3–36 in the renal vasculature or glomeruli is indeed mediated by DPP IV. Also consistent with this hypothesis is the observation that incubation of isolated preglomerular microvessels as well as isolated glomeruli with PYY1–36 results in the rapid appearance of PYY3–36. The conversion of PYY1–36 to PYY3–36 by both preglomerular microvessels and glomeruli is inhibited by P32/98, indicating that this metabolic conversion is mediated by DPP IV.
In SHR kidneys (i.e., genetically susceptible kidneys) but not WKY kidneys activation by the Gi signal transduction pathway augments Ang II-induced renal vasoconstriction regardless of the agonist/receptor system used to stimulate Gi. For example, stimulation of Gi-coupled 
2-adrenoceptors with the selective agonist UK14,304 (Gao et al., 2003) or stimulation of Gi-coupled Y1Rs with the selective agonist LPNPY (Dubinion et al., 2006b) enhances renovascular responses to Ang II in SHR kidneys, while having no affect on renovascular responses to Ang II in WKY kidneys. Likewise, stimulation of Gi-coupled A1 receptors with the selective agonist cyclopentyladenosine also potentiates renovascular responses to Ang II in SHR but not WKY kidneys (E. K. Jackson, unpublished observation). The genetic defect in SHR kidneys that gives rise to this phenomenon is not entirely clear; however, our previously published results suggest that coincident signaling at the level of phospholipase C plays an important role in allowing activation of the Gi pathway to enhance renovascular responses to Ang II in SHR but not WKY kidneys (Jackson et al., 2005). We previously demonstrated (Dubinion et al., 2006a,b) that activation of Y1Rs or, indeed, of any Gi-coupled receptor has little or no ability to enhance renovascular responses to Ang II in WKY kidneys. Thus, inhibition of DPP IV should not influence the interaction between Ang II and PYY1–36 in WKY kidneys because there is no interaction to influence. Indeed, as shown in Fig. 5, PYY1–36 does not enhance Ang II-induced renal vasoconstriction either in the absence or presence of P32/98.
The hypothesis tested in this study has potentially significant pharmacological implications. The Food and Drug Administration recently approved an inhibitor of DPP IV for use in type 2 diabetic individuals, a population prone to excessive food intake, obesity, hypertension, and impaired renal function. Our hypothesis provides a cautionary red flag because inhibitors of DPP IV would be expected to cause decreased renal blood flow and hypertension in obese type 2 diabetic individuals whose kidneys happen to be "SHR-like", i.e., sensitive to the Ang II-enhancing effects of Y1Rs. Food intake increases plasma levels of PYY1–36 by as much as 10-fold after a large, fatty meal (Pappas et al., 1986; Armstrong et al., 1991; Fu-Cheng et al., 1997; Anini et al., 1999; MacIntosh et al., 1999; Teixeira et al., 2001; Korner et al., 2005). In addition, food intake and obesity are associated with activation of the renin-angiotensin system (Corman et al., 1988; Cassis et al., 1998; Ahmed et al., 2005). Therefore, frequent intake of large, fatty, calorie-laden meals associated with obese-prone eating patterns in type 2 diabetics would 1) increase time-averaged circulating levels of PYY1–36 because the intestinal L-cells would be driven to release larger pulses of PYY1–36 (because of larger meals) and more frequently pulses of PYY1–36 (because of more frequent large meals) and 2) stimulate the renin-angiotensin system. In those individuals whose kidneys are SHR-like (i.e., are sensitive to the enhancing effects of Y1R agonists on Ang II-induced renal vasoconstriction), DPP IV inhibitors, by the mechanisms explored in the present study, may increase renal vascular resistance and arterial blood pressure. However, whether there exists a subpopulation of type 2 diabetic individuals with SHR-like kidneys is presently unknown, and therefore the clinical significance of our findings is currently hypothetical.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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.
Address correspondence to: Dr. Edwin K. Jackson, Center for Clinical Pharmacology, 100 Technology Dr., Suite 450, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219. E-mail: edj{at}pitt.edu
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