Role of Renal Dipeptidyl Peptidase IV

描述(申请人提供)：二肽基肽酶IV(DPPIV)抑制剂是一类治疗2型糖尿病的新药。由于这类药物[例如西格列汀(Januvia)]能够持续降低HbA1c，低血糖风险低，对体重几乎没有影响，DPPIV抑制剂很可能被广泛用于控制世界范围内的2型糖尿病和代谢综合征的流行。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，数以千万计的患者将服用DPPIV抑制剂，其中许多人将在他们的余生中；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。根据它们的作用机制，我们预计DPPIV抑制剂将表现出不良反应。DPPIV可代谢胰岛素类激素[如胰升糖素样肽-1(GLP-1)和葡萄糖依赖的促胰岛素肽(GIP)]，因此DPPIV抑制剂可提高循环中的胰岛素水平，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而发挥抗糖尿病作用。然而，DPPIV至少代谢35种内源性底物，抑制这些底物代谢的药理学后果大多尚不清楚。值得我们特别关注的是，DPPIV将Y1受体(Y1R)激动剂神经肽Y1-36(NPY1-36)和YY1-36(PYY1-36)分别转化为选择性Y2受体(Y2R)激动剂NPY3-36和PYY3-36。实际上，DPPIV在逻辑上可以被命名为“NPY转换酶”，因为NPY1-36的DPPIV的kcat/Km分别是GLP-1和GIP的36倍和73倍。显然，DPPIV抑制剂可能会改变Y1R和Y2R刺激之间的平衡，这可能会对肾脏产生不利影响。例如，我们之前发表的工作表明，DPPIV抑制通过Y1R介导的作用增强血管紧张素II诱导的遗传易感肾脏的肾血管收缩。此外，我们最近获得的初步数据表明，NPY1-36和PYY1-36可(通过Y1R激活)刺激来自遗传易感肾脏的肾小球前血管平滑肌细胞(PGVSMCs)和肾小球系膜细胞(GMC)的增殖和细胞外基质的产生，而抑制DPPIV可增强这些作用。我们的初步数据还表明，支架蛋白RACK1在遗传易感肾脏的PGVSMCs和GMCs中激活和DPPIV抑制的更大影响有关。这些初步发现促使我们检验以下假设：在PGVSMCs和GMCs中抑制DPPIV可以阻止NPY1-36和PYY1-36的局部代谢，从而增加PGVSMCs和GMCs中Y1R的激活。在遗传易感的肾脏PGVSMCs和GMCs中，这一机制导致RACK1介导的细胞增殖和细胞外基质产生增加，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的抑制剂代表了一类用于治疗2型糖尿病的新型抗糖尿病药物，这类药物，例如西格列汀(Januvia(R)；最近获得FDA批准)可以显著和持续地降低HbA1c，且低血糖风险低，对体重几乎没有影响。DPPIV抑制剂的这些特点，加上对噻唑烷二酮类药物安全性的新出现的不确定性，使得DPPIV抑制剂极有可能被广泛用于控制世界范围内的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降糖药。因为在不久的将来，每年将有1亿名患者服用DPPIV抑制剂，而且服用DPPIV抑制剂的患者将在其余生中继续服用这些药物，因此有必要更充分地了解与DPPIV抑制相关的长期风险。DPPIV抑制剂在高血压和代谢综合征环境中的长期风险特别令人担忧，因为这些情况经常是2型糖尿病患者的共病。本提案研究了关键问题，即抑制肾脏DPPIV是否会对患有高血压的动物的肾脏产生不利影响，无论是否有代谢综合征，这些代谢综合征都可能加速糖尿病肾脏疾病的发展。

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.