Renoprotective effect of increased PKG activity in diabetic nephropathy

增加 PKG 活性对糖尿病肾病的肾脏保护作用

• 批准号: 8141677
• 负责人: Shuxia Wang
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141677
• 关键词: Affect; Albuminuria; Attenuated; Clinic; Complication; Complications of Diabetes Mellitus; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Deposition; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dialysis procedure; Down-Regulation; Drug usage; End stage renal failure; Erectile dysfunction; Extracellular Matrix; Fibrosis; Gene Expression; Genetic; Glucose; Growth Factor; Health Expenditures; Healthcare; Healthcare Systems; High Prevalence; Human; Hyperglycemia; In Vitro; Injury; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Link; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Patients; Play; Population; Production; Protein Kinase; Proteins; Quality of life; Role; Signal Transduction; Testing; Therapeutic; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Translating; Up-Regulation; Veterans; Work; clinically relevant; diabetic; glomerular basement membrane; glomerulosclerosis; improved; in vivo; inhibitor/antagonist; kidney cell; male; mesangial cell; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; phosphodiesterase V; prevent; pulmonary arterial hypertension; response; sildenafil; success

DESCRIPTION (provided by applicant): Diabetic nephropathy is the single most common cause of end-stage renal failure, and is highly prevalent in both type 1 and type 2 diabetics. Hyperglycemia has been suggested to play a critical role in the pathogenesis of diabetic nephropathy. Transforming growth factor-2 (TGF-2) is a major effector leading to renal fibrosis in response to hyperglycemia. TGF-2 is expressed as a biologically inactive form and must be converted to its active form to elicit fibrogenic effects. Thrombospondin1 (TSP1) has been identified as the molecular regulator of TGF-2 activation under diabetic conditions. TSP1-mediated TGF-2 activation is involved in the development of experimental diabetic nephropathy and also plays a role in human diabetic nephropathy. Preliminary data demonstrate a novel inhibitory effect of cGMP-dependent protein kinase (PKG) on glucose-induced TSP1 expression and TSP1-mediated TGF-2 activation in mesangial cells, suggesting a therapeutic potential of PKG in diabetic nephropathy. The proposed studies will test whether genetically or pharmacologically increased PKG activity prevents the development of diabetic nephropathy through inhibition of TSP1-mediated TGF-2 activation in different diabetic mouse models. Specific Aim 1 will determine the mechanisms by which high glucose down-regulates PKG activity in kidney cells in vitro and its role in glucose-induced TSP1 expression, TGF-2 levels/activity, and extracellular matrix (ECM) production. Specific Aim 2 will determine whether increased PKG activity prevents the development of diabetic nephropathy in vivo. These studies will establish the significance of PKG in the development of diabetic nephropathy. Importantly, utilization of sildenafil (an inhibitor of cGMP specific phosphodiesterase 5) to increase PKG activity in the proposed studies is translational and relevant to human therapy. Sildenafil is a drug used to treat erectile dysfunction (ED, another diabetic complication in male patients) and pulmonary arterial hypertension (PAH) in clinic. The current proposed studies will test a novel potential application of sildenafil in the treatment of diabetic nephropathy in different diabetic mouse models. Therefore, these studies have significant clinical relevance, and will lead to the development of novel therapies to attenuate/treat diabetic nephropathy, a major complication of diabetes. PUBLIC HEALTH RELEVANCE: More than 20% of veterans or one million veterans who use VA health care system are affected by diabetes. Veterans also have very high prevalence of diabetic complications, including nephropathy. Nephropathy is a major complication of diabetes which leads to considerable morbidity and mortality. Despite current improved treatments, significant numbers of patients with albuminuria progress to end stage renal disease which requires dialysis or kidney transplantation. This proposal aims at defining the novel roles for PKG, a cGMP- dependent protein kinase, in the development of diabetic nephropathy and testing the novel therapeutic potential of genetically or pharmacologically increased PKG activity in attenuating diabetic nephropathy in different mouse models of diabetes. The success of this proposal will benefit the veterans' health care: improving the quality of life of veterans and reducing the health care expenditures in the VA health care system.

描述（由申请人提供）： 糖尿病性肾病是终末期肾衰竭的最常见原因，在1型和2型糖尿病患者中都非常普遍。已经建议高血糖在糖尿病肾病的发病机理中起关键作用。转化生长因子2（TGF-2）是导致肾纤维化响应高血糖的主要效应子。 TGF-2表示为生物学上的非活性形式，必须转化为活性形式以引起纤维纤维效应。在糖尿病条件下，血小板传播1（TSP1）已被确定为TGF-2激活的分子调节剂。 TSP1介导的TGF-2激活与实验性糖尿病性肾病的发展有关，并且在人类糖尿病性肾病中也起作用。初步数据证明了CGMP依赖性蛋白激酶（PKG）对葡萄糖诱导的TSP1表达和TSP1介导的TGF-2激活的新型抑制作用，这表明PKG在糖尿病性肾病中的治疗潜力。拟议的研究将通过在不同糖尿病小鼠模型中抑制TSP1介导的TGF-2激活来测试遗传或药理上增加的PKG活性是否通过抑制TSP1介导的TGF-2激活来阻止糖尿病性肾病的发展。具体目标1将确定高葡萄糖在体外肾细胞中降低PKG活性的机制及其在葡萄糖诱导的TSP1表达，TGF-2水平/活性和细胞外基质（ECM）产生中的作用。具体目标2将确定PKG活性增加是否阻止体内糖尿病性肾病的发展。这些研究将确定PKG在糖尿病性肾病发展中的重要性。重要的是，在拟议的研究中，西地那非（CGMP特异性磷酸二酯酶5）的利用（CGMP特异性磷酸二酯酶5）与人类治疗相关。西地那非是一种用于治疗勃起功能障碍（ED，男性患者的另一种糖尿病并发症）和肺动脉高压（PAH）的药物。当前提出的研究将测试西地那非在不同糖尿病小鼠模型中治疗糖尿病性肾病的新型潜在应用。因此，这些研究具有显着的临床相关性，并将导致衰减/治疗糖尿病性肾病的新型疗法发展，这是糖尿病的主要并发症。 公共卫生相关性： 超过20％的退伍军人或使用VA医疗保健系统的一百万退伍军人受糖尿病的影响。退伍军人还具有包括肾病在内的糖尿病并发症患病率很高。肾病是糖尿病的主要并发症，导致了相当大的发病率和死亡率。尽管目前的治疗方法改善了，但大量的蛋白尿患者发展为终止肾脏疾病，需要透析或肾脏移植。该提案旨在定义PKG（一种CGMP依赖性蛋白激酶）在糖尿病性肾病的发展中的新作用，并测试遗传学或药理上PKG活性在减弱糖尿病模型中遗传学或药理上增加PKG活性的新型治疗潜力。该提案的成功将使退伍军人的医疗保健受益：改善退伍军人的生活质量，并减少VA医疗保健系统中的医疗保健支出。