Modulation of Diabetic Kidney Growth/ Hypertrophy

描述（由申请人提供）：早期1型糖尿病患者肾小球滤过率（GFR）升高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轻肾损害，预防肾衰竭。我们的研究表明早期肾小球高滤过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，从而较少的盐到达黄斑致密，导致小管肾小球反馈激活，GFR增加和超滤过。此外，异常的近端小管重吸收导致盐悖论，高盐摄入会降低GFR。但是仅仅是肾脏的生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开始于有丝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，即最初的增生随后是肥大。这种机制类似于衰老的机制。我们假设糖尿病患者近端小管的衰老样阻滞会影响细胞分化和反应性状态。对盐重吸收反应的改变不仅是基底肾小球高滤过的基础，也是盐悖论的基础。以衰老成纤维细胞为例，衰老的近端小管细胞会表现出氧化应激增加，增加糖尿病炎症环境，蛋白质水解活性降低，促进晚期糖尿病肥大，细胞外基质产生和重塑扭曲，导致纤维化。我们假设皮质小管细胞的衰老样阻滞/表型不仅是高滤过的一个促成因素，也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盐对皮质小管、基底小管高重吸收和肾小球高滤过的衰老样停滞/表型的影响，以及盐悖论。

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.