Modulation of Diabetic Kidney Growth/Hypertrophy

描述(由申请人提供)：早期1型糖尿病患者的肾小球滤过率(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高滤过可减少肾损害，预防肾功能衰竭。我们的工作表明，早期肾小球高滤过可能是肾脏生长的结果。伴随这种生长的是近端小管盐重吸收的异常增加，到达致密黄斑的盐分减少，导致小管小球反馈激活，肾小球滤过率增加和高滤过。此外，近端小管的异常重吸收导致盐悖论，高盐摄入量会降低GFR。但是，仅仅肾脏的增长就足以解释糖尿病并发症的进展吗？糖尿病近端小管的早期生长是丝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期细胞周期停滞，即最初的增殖和随后的肥大。这一机制类似于衰老。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状态。对盐重吸收反应的改变不仅是基础肾小球高滤过的基础，也是盐悖论的基础。以衰老的成纤维细胞为模型，衰老的近端小管细胞会表现出氧化应激增加，增加糖尿病的炎症环境，降低促进糖尿病晚期肥大的蛋白分解活性，并扭曲细胞外基质的产生和有助于纤维化的重塑。我们推测，皮质小管细胞的衰老样停滞/表型不仅是高滤过的一个促成因素，而且是其他下游糖尿病并发症的一个促成因素。基因敲除将被用于调节早期糖尿病肾脏的生长/肥大。我们将通过分子和生理参数来评估其对皮质小管衰老样停滞/表型、基础肾小管高重吸收和肾小球高滤过以及盐悖论的影响。

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.