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: 8287999
• 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/8287999
• 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.

描述（由申请人提供）： 糖尿病肾病是终末期肾衰竭的最常见原因，在1型和2型糖尿病患者中非常普遍。高血压在糖尿病肾病的发病机制中起重要作用。转化生长因子-2（TGF-2）是高血糖导致肾纤维化的主要效应因子。TGF-2以生物学上无活性的形式表达，必须转化为其活性形式以引起纤维化作用。血小板反应蛋白1（TSP 1）已被鉴定为糖尿病条件下TGF-2活化的分子调节剂。TSP 1介导的TGF-2活化参与实验性糖尿病肾病的发展，并且在人类糖尿病肾病中也起作用。初步数据表明，cGMP依赖性蛋白激酶（PKG）对葡萄糖诱导的TSP 1表达和TSP 1介导的TGF-2在系膜细胞中的活化具有新的抑制作用，表明PKG在糖尿病肾病中的治疗潜力。拟议的研究将测试在不同的糖尿病小鼠模型中，基因或非基因增加的PKG活性是否通过抑制TSP 1介导的TGF-2活化来预防糖尿病肾病的发展。具体目标1将确定高葡萄糖在体外下调肾细胞中PKG活性的机制及其在葡萄糖诱导的TSP 1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将确定是否增加PKG活性防止体内糖尿病肾病的发展。这些研究将确定PKG在糖尿病肾病发展中的意义。重要的是，在拟定研究中使用西地那非（cGMP特异性磷酸二酯酶5抑制剂）增加PKG活性是一种转化，与人体治疗相关。西地那非是临床上用于治疗男性糖尿病并发症勃起功能障碍（艾德）和肺动脉高压（PAH）的药物。目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肾病的新的潜在应用。因此，这些研究具有显著的临床相关性，并将导致开发新的疗法来减轻/治疗糖尿病肾病，糖尿病的主要并发症。