Modulation of Diabetic Kidney Growth/Hypertrophy

调节糖尿病肾脏生长/肥大

• 批准号: 7031956
• 负责人: JOSEPH SATRIANO
• 金额: $ 13.86万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031956
• 关键词: cell cycle; cell cycle proteins; cell differentiation; cell senescence; diabetes mellitus; disease /disorder model; enzyme inhibitors; extracellular matrix; fibroblasts; fibrosis; glomerular filtration; kidney cell; kidney hypertrophy; laboratory mouse; laboratory rat; medical complication; nephrogenesis; oxidative stress; phenotype; protein kinase; protein kinase C; proteolysis; renal tubular transport; renal tubule; salts; streptozotocin; western blottings

DESCRIPTION (provided by applicant): An increase in glomerular filtration rate (GFR) in early type 1 diabetes is a risk factor for progression to end- stage renal disease. Preventing or treating early glomerular hyperfiltration may reduce kidney damage and prevent kidney failure. Our work indicates that early glomerular hyperfiltration can be the consequence of kidney growth. This growth is accompanied by an abnormal increase in proximal tubule salt reabsorption whereby less salt reaches the macula densa resulting in activation of tubuloglomerular feedback, increased GFR and hyperfiltration. Further, aberrant proximal tubule reabsorption causes the salt paradox, with a high salt intake decreasing GFR. But is kidney growth alone sufficient to account for the progression of diabetic complications? Early growth of the diabetic proximal tubule begins as a mitogen-induced growth response followed by cyclin kinase inhibitor mediated G1 cell cycle arrest, i.e., initial hyperplasia followed by hypertrophy. This mechanism resembles that of senescence. We hypothesize that a senescent-like arrest of the proximal tubules in diabetes would affect the state of cell differentiation and responsiveness. A change in response to salt reabsorption would form the basis not only for basal glomerular hyperfiltration but also for the salt paradox. Using senescent fibroblasts as a paradigm, senescent proximal tubule cells would display increased oxidative stress, adding to the diabetic inflammatory environment, reduced proteolytic activity that would promote later stage diabetic hypertrophy, and skewed extracellular matrix production and remodeling that would contribute to fibrosis. We hypothesize that a senescent-like arrest/phenotype of cortical tubule cells is a contributing factor not only to hyperfiltration, but to other downstream diabetic complications. Gene knockout will be used to modulate early diabetic kidney growth/hypertrophy. We will evaluate the consequences on the senescent-like arrest/phenotype of cortical tubules, basal tubular hyperreabsorption and glomerular hyperfiltration, and the salt paradox via molecular and physiologic parameters.

描述（由申请人提供）：早期1型糖尿病的肾小球滤过率（GFR）增加是进展为终末期肾病的危险因素。预防或治疗早期肾小球超滤可减少肾损伤和预防肾衰竭。我们的工作表明早期肾小球超滤可能是肾脏生长的结果。这种生长伴随着近端小管盐重吸收的异常增加，由此较少的盐到达致密斑，导致小管肾小球反馈的激活、GFR增加和超滤。此外，异常的近端小管重吸收导致盐悖论，高盐摄入降低GFR。但是，单凭肾脏生长是否足以解释糖尿病并发症的进展？糖尿病近端小管的早期生长开始于促分裂原诱导的生长反应，随后是细胞周期蛋白激酶抑制剂介导的G1细胞周期停滞，即，最初增生，随后肥大。这种机制类似于衰老。我们假设糖尿病患者近端小管的衰老样停滞会影响细胞分化和反应性的状态。对盐重吸收的反应的变化不仅是基础肾小球超滤的基础，也是盐悖论的基础。使用衰老的成纤维细胞作为范例，衰老的近端小管细胞将显示增加的氧化应激，增加糖尿病炎症环境，降低的蛋白水解活性，这将促进后期糖尿病肥大，以及扭曲的细胞外基质产生和重塑，这将有助于纤维化。我们假设皮质小管细胞的衰老样停滞/表型不仅是超滤的一个促成因素，而且是其他下游糖尿病并发症的一个促成因素。基因敲除将用于调节早期糖尿病肾脏生长/肥大。我们将通过分子和生理参数评估皮质小管衰老样停滞/表型、基底小管重吸收和肾小球超滤以及盐悖论的后果。