Role of Renal Dipeptidyl Peptidase IV

肾二肽基肽酶 IV 的作用

• 批准号: 8133626
• 负责人: EDWIN Kerry JACKSON
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133626
• 关键词: 2,4-thiazolidinedione; Adverse effects; Affect; Agonist; Angiotensin II; Animals; Antidiabetic Drugs; Blood Vessels; Body Weight; Cell Proliferation; Cells; Characteristics; Collagen; Comorbidity; DNA biosynthesis; Data; Development; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Enzymes; Equilibrium; Europe; Extracellular Matrix; FDA approved; Functional disorder; Future; Gastric Emptying; Gastric Inhibitory Polypeptide; Genes; Genetic; Glomerular Mesangial Cell; Glucagon; Glycosylated hemoglobin A; Growth; Hypertension; Hypoglycemia; Inbred SHR Rats; Inbred WKY Rats; Insulin; Kidney; Kidney Diseases; Mediating; Messenger RNA; Metabolic syndrome; Metabolism; Names; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Patients; Peptides; Pharmaceutical Preparations; Plasmids; Predisposition; Production; Proteins; Publishing; Rattus; Receptor Activation; Rest; Risk; Role; Safety; Sales; Scaffolding Protein; Small Interfering RNA; Smooth Muscle Myocytes; Testing; Thiazolidinediones; Time; Transfection; Uncertainty; Western Blotting; Work; base; diabetic; glomerulosclerosis; glucagon-like peptide; incretin hormone; inhibitor/antagonist; normotensive; novel; pandemic disease; prevent; receptor; small hairpin RNA; vasoconstriction

DESCRIPTION (provided by applicant): Dipeptidyl peptidase IV (DPPIV) inhibitors are a new class of drugs for treatment of type 2 diabetes. Because drugs in this class [e.g., sitagliptin (Januvia)] afford sustained reductions in HbA1c with a low risk of hypoglycemia and little effect on body weight, it is likely that DPPIV inhibitors will be extensively employed to manage the world-wide pandemic of type 2 diabetes and the metabolic syndrome. Indeed, sitagliptin is already the 2nd leading branded oral antidiabetic agent in the USA. In the near future, tens of millions of patients will be taking DPPIV inhibitors, many for the rest of their lives; thus, we should strive to fully understand the risks, both short-term and long-term, associated with DPPIV inhibition. Based on their mechanism of action, we anticipate that DPPIV inhibitors will express adverse effects. DPPIV metabolizes incretin hormones [e.g., glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and consequently DPPIV inhibitors raise circulating levels of incretins and thereby exert antidiabetic actions by increasing insulin release, inhibiting glucagon secretion and retarding gastric emptying. However, DPPIV metabolizes at least 35 endogenous substrates, and the pharmacological consequences of inhibiting the metabolism of these substrates are mostly unknown. Of particular concern to us is the fact that DPPIV converts neuropeptide Y1-36 (NPY1-36) and peptide YY1-36 (PYY1-36), which is Y1 receptor (Y1R) agonists, to NPY3-36 and PYY3-36, respectively, which are selective Y2 receptor (Y2R) agonists. Indeed, DPPIV could just as logically be named "NPY Converting Enzyme" because the kcat/Km of DPPIV for NPY1-36 is approximately 36-fold and 73-fold greater for NPY1-36 compared with GLP-1 and GIP, respectively. Clearly DPPIV inhibitors may alter the balance between Y1R and Y2R stimulation, and this may have adverse renal consequences. For example, our previously published work shows that DPPIV inhibition augments angiotensin II-induced renal vasoconstriction in genetically-susceptible kidneys via a Y1R mediated action. Moreover, our recently obtained pilot data suggest that NPY1-36 and PYY1-36 stimulate (via Y1R activation) proliferation of, and extracellular matrix production by, preglomerular vascular smooth muscle cells (PGVSMCs) and glomerular mesangial cells (GMCs) obtained from genetically-susceptible kidneys and that inhibition of DPPIV augments these effects. Our pilot data also suggest that the scaffold protein RACK1 is responsible for the greater effects of Y1R activation and DPPIV inhibition in PGVSMCs and GMCs from genetically-susceptible kidneys. These preliminary findings motivate us to test the following hypothesis: Inhibition of DPPIV in PGVSMCs and GMCs prevents the local metabolism of NPY1-36 and PYY1-36, thus increasing Y1R activation in PGVSMCs and GMCs. In PGVSMCs and GMCs from kidneys that are genetically-susceptible, this mechanism leads to RACK1 mediated enhancement of cellular proliferation and extracellular matrix production, thus increasing the risk of glomerulosclerosis and renal dysfunction. PUBLIC HEALTH RELEVANCE: Inhibitors of DPPIV represent a novel class of antidiabetic drugs for treatment of Type 2 diabetes, and drugs in this class, for example sitagliptin (Januvia(R); recently FDA approved), afford significant and sustained reductions in HbA1c with a low risk of hypoglycemia and little effect on body weight. These characteristics of DPPIV inhibitors, along with the emerging uncertainty regarding the safety of thiazolidinediones, make it highly likely that DPPIV inhibitors will be extensively employed to manage the world-wide pandemic of type 2 diabetes; indeed, the DPPIV inhibitor sitagliptin is the 2nd leading branded oral antidiabetic agent in the USA. Because in the near future >100 million patients yearly will be taking DPPIV inhibitors and because patients who are prescribed DPPIV inhibitors will continue to consume them for the remainder of their lives, there is some urgency to more fully understand the long-term risks associated with DPPIV inhibition. The long-term risks of DPPIV inhibitors in the setting of hypertension and the metabolic syndrome are of particular concern because frequently these conditions are co-morbidities in type 2 diabetics. The present proposal examines the critical issue as to whether inhibition of renal DPPIV has adverse effects on the kidneys of animals with hypertension, with and without the metabolic syndrome that could accelerate the development of diabetic renal disease.

描述（由申请人提供）：二肽基肽酶IV（DPPIV）抑制剂是一类用于治疗2型糖尿病的新药。因为这类药物[例如，西他列汀（捷诺维）]提供HbA 1c的持续降低，低血糖风险低，对体重影响小，因此DPPIV抑制剂很可能被广泛用于控制2型糖尿病和代谢综合征的全球流行。事实上，西格列汀已经是美国第二大品牌口服降糖药。在不久的将来，将有数千万患者服用DPPIV抑制剂，其中许多人将终生服用;因此，我们应该努力充分了解与DPPIV抑制相关的短期和长期风险。 基于其作用机制，我们预计DPPIV抑制剂将表现出不良反应。DPPIV代谢肠促胰岛素激素[例如，胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素肽（GIP）]，因此DPPIV抑制剂提高肠促胰岛素的循环水平，从而通过增加胰岛素释放、抑制胰高血糖素分泌和延迟胃排空发挥抗糖尿病作用。然而，DPPIV代谢至少35种内源性底物，抑制这些底物代谢的药理学后果大多未知。我们特别关注的是DPPIV将神经肽Y1-36（NPY 1 -36）和肽YY 1 -36（PYY 1 -36）（其为Y1受体（Y1 R）激动剂）分别转化为NPY 3 -36和PYY 3 -36（其为选择性Y2受体（Y2 R）激动剂）。实际上，DPPIV可以在逻辑上被命名为“NPY转化酶”，因为与GLP-1和GIP相比，DPPIV对NPY 1 - 36的kcat/Km分别约为36倍和73倍。 显然，DPPIV抑制剂可能会改变Y1 R和Y2 R刺激之间的平衡，这可能会对肾脏产生不良影响。例如，我们先前发表的工作表明，DPPIV抑制增强血管紧张素II诱导的肾血管收缩在遗传易感的肾脏通过Y1 R介导的行动。此外，我们最近获得的试点数据表明，NPY 1 -36和PYY 1 -36刺激（通过Y1 R激活）增殖，细胞外基质的生产，肾小球前血管平滑肌细胞（PGVSMCs）和肾小球系膜细胞（GMCs）从遗传易感的肾脏和DPPIV的抑制增强这些效果。我们的试验数据还表明，支架蛋白RACK 1是负责更大的影响Y1 R激活和DPPIV抑制PGVSMC和GMC从遗传易感的肾脏。这些初步发现促使我们验证以下假设：PGVSMC和GMC中DPPIV的抑制阻止了NPY 1 -36和PYY 1 -36的局部代谢，从而增加了PGVSMC和GMC中Y1 R的激活。在来自遗传易感肾脏的PGVSMC和GMC中，该机制导致RACK 1介导的细胞增殖和细胞外基质产生的增强，从而增加肾小球硬化和肾功能障碍的风险。 公共卫生相关性：DPPIV抑制剂代表了一类新的用于治疗2型糖尿病的抗糖尿病药物，并且这类药物，例如西他列汀（Januvia;最近FDA批准），提供了HbA 1c的显著和持续的降低，低血糖风险低，对体重影响小。DPPIV抑制剂的这些特征，沿着新出现的有关噻唑烷二酮安全性的不确定性，使得DPPIV抑制剂极有可能被广泛用于控制全球范围内的2型糖尿病大流行;事实上，DPPIV抑制剂西格列汀是美国第二大品牌口服抗糖尿病药物。因为在不久的将来，每年将有> 1亿患者服用DPPIV抑制剂，并且因为处方DPPIV抑制剂的患者将在其余生中继续服用它们，所以更全面地了解与DPPIV抑制相关的长期风险具有一定的紧迫性。DPPIV抑制剂在高血压和代谢综合征背景下的长期风险特别值得关注，因为这些疾病通常是2型糖尿病患者的合并症。本提案审查了抑制肾脏DPPIV是否对高血压动物的肾脏产生不良影响的关键问题，无论是否存在可能加速糖尿病肾病发展的代谢综合征。