MATRIX METALLOPROTEINASES IN DIABETIC KIDNEY DISEASE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在1型糖尿病患者中，有20年病史的患者中约50%会发生糖尿病肾病。此外，糖尿病肾病是美国终末期肾病(ESRD)最常见的原因，占所有新诊断的ESRD病例的30%-40%。在美国，糖尿病患者与ESRD相关的成本估计为5.1万美元/患者年。糖尿病合并肾功能衰竭患者每年的护理费用估计为30-40亿美元。总而言之，这些统计数据突出了糖尿病肾病在这个国家的重大医疗和财务影响。在那些发生肾功能障碍的人中，已经确定了几个发生肾脏疾病的危险因素，包括糖尿病病程、确诊年龄、种族、全身性或肾小球高血压、血糖控制不良、肾脏疾病的遗传易感性和饮食结构。然而，糖尿病肾病发生和发展的确切致病机制仍然知之甚少。此外，没有统一的假设来解释1型糖尿病患者肾脏疾病的高发病率。糖尿病肾病的发展被描述为一个5阶段的过程，从肾小球高滤过和肾肥大(阶段1)，到肾小球基底膜(GBM)增厚和系膜扩张(阶段2)，到微量蛋白尿并最终肾小球滤过率(GFR)下降(阶段3)，到单纯蛋白尿并严重高血压和中到重度肾功能不全的后遗症(阶段4)，最后是终末期肾病(ESRD)。有人假设，GBM厚度和含量的早期变化最终会影响GBM的过滤特性，首先导致尿白蛋白排泄增加，最终导致明显的蛋白尿。这些措施是我们临床上唯一可以检测到肾脏损害的指标。由于细胞外基质(ECM)在肾脏中降解的主要生理调节因子是基质金属蛋白酶(MMPs)，细胞外基质合成和降解的失衡可能导致ECM代谢改变，从而导致肾小球瘢痕形成和肾功能下降。目前，来自动物模型的数据表明，在糖尿病肾病中，基质金属蛋白酶活性可能下调，允许过度的ECM沉积和系膜扩张。链脲佐菌素(STZ)治疗的大鼠的研究证实了这一点，在这些研究中，肾脏组织中MMPs的表达受到抑制，而金属蛋白酶组织抑制物(TIMP-1)的表达增加。然而，来自人类研究的数据表明，这是一种更复杂的相互作用。例如，在2型糖尿病中，微量白蛋白尿的发生可能是由于血浆中92 kDa的基质金属蛋白酶和基质金属蛋白酶-9浓度的升高，而血清基质金属蛋白酶-9浓度的升高与肾脏疾病的发生和发展有关。此外，血清基质金属蛋白酶-9浓度与尿足细胞数相关，尿足细胞数是肾功能障碍的一个非常早期的标志。虽然在一种涉及ECM积聚和瘢痕形成的疾病的发病机制中，MMPs活性的增加似乎与直觉相反，但最近的数据表明，MMPs的一个重要作用，除了对ECM重塑的直接影响外，是否释放或激活了促纤维化细胞因子和生长因子，如转化生长因子？转化生长因子-β、肿瘤坏死因子-α、胰岛素样生长因子和肝素结合性表皮生长因子。作为这种活动的结果，某些MMPs的高水平可能会增强肾组织对生长因子的可获得性。不幸的是，目前尚缺乏糖尿病肾病中基质金属蛋白酶活性与生长因子/细胞因子作用之间的联系。微量白蛋白尿对进展为临床肾病的预测价值并不准确。尿白蛋白排泄量(UAE)没有增加的患者显然建议这样做，但他们仍会发展为晚期肾脏损害。因此，更好地了解糖尿病肾病的潜在发病机制是必要的，以便制定策略，在早期阶段发现肾病，并开发和实施更多靶向的分子特异性治疗。糖尿病控制和并发症试验(DCCT)的结果表明，在接受强化治疗的糖尿病患者中，经过7年的严格血糖控制，调整后的平均蛋白尿风险降低了56%，微量蛋白尿的风险降低了43%。这些结果证实了糖尿病肾病发展的一个主要危险因素是慢性高血糖。此外，DCCT表明，血糖控制的长期改善可以中断肾脏病理的进展。根据DCCT的结果，以及动物模型中关于高血糖介导的基质金属蛋白酶分泌和作用的失调在肾脏病理中的重要性的新证据，我们假设：1)葡萄糖稳态直接参与人类基质金属蛋白酶系统的调节；2)由于慢性高血糖，肾脏中基质金属蛋白酶活性的失调有助于糖尿病肾病的发生和发展；以及3)临床可检测到的基质金属蛋白酶浓度异常将预示糖尿病肾病的发生，表明基质金属蛋白酶分析可能是糖尿病肾病的有用生物标记物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Among patients with type 1 DM, diabetic nephropathy develops in ~ 50 % of patients with a 20 year history of disease. Moreover, diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, contributing to 30-40% of all newly diagnosed cases of ESRD. In the US, costs associated with ESRD for patients with diabetes are estimated at $51,000/patient-year. Yearly costs of care for diabetic patients with renal failure have been estimated at 3-4 billion dollars. Together, these statistics highlight the significant medical and financial impact of diabetic nephropathy in this country. Among those individuals who develop renal dysfunction, several risk factors for the development of renal disease have been identified, including duration of diabetes, age at diagnosis, race, systemic or glomerular hypertension, poor glycemic control, genetic predisposition to kidney disease and dietary composition. However, the precise pathogenic mechanisms involved in the initiation and progression of diabetic nephropathy remain poorly understood. Moreover, no unifying hypothesis exists to explain the high incidence of renal disease among patients with type 1 DM. The development of diabetic nephropathy has been described as a 5-stage process, progressing from a condition of glomerular hyperfiltration and nephromegaly (Stage 1), to glomerular basement membrane (GBM) thickening and mesangial expansion (Stage 2), to microalbuminuria and eventual decline in glomerular filtration rate (GFR) (Stage 3), to frank proteinuria with severe hypertension and sequelae of moderate to severe renal insufficiency (stage 4), to eventual ESRD (Stage 5). It has been hypothesized that the early changes in GBM thickness and content ultimately affect filtration properties of the GBM, leading first to increased urinary albumin excretion, and eventually to frank proteinuria. Such measures are our only clinically detectible indicators of renal damage. Because the major physiologic regulators of extracellular matrix (ECM) degradation in the kidney are matrix metalloproteinases (MMPs), an imbalance in extracellular matrix synthesis and degradation could result in altered ECM turnover, which could lead to glomerular scarring and a decline in renal function. Currently, data from animal models suggest that in diabetic nephropathy, MMP activity may be down-regulated, allowing for excess ECM deposition and mesangial expansion. This is supported by studies in streptozotocin (STZ)-treated rats, in which MMPs were depressed and tissue inhibitors of metalloproteinases (TIMP-1) were increased in renal tissue. However, the data from human studies suggest a more complex interaction. For instance, in type 2 DM, the development of microalbuminuria may be heralded by an increase in plasma concentrations of the 92 kDa MMP, MMP-9, and elevated MMP-9 serum concentrations have been correlated with the onset and progression of renal disease. Furthermore, MMP-9 serum concentrations correlate with urine podocyte numbers, a very early marker of renal dysfunction. While an increase in MMP activity seems counterintuitive in the pathogenesis of a disorder that involves enhanced ECM accumulation and scarring, recent data suggests that an important action of MMPs, beyond their direct effects on ECM remodeling, is the release or activation of pro-fibrotic cytokines and growth factors, such as transforming growth factor-? (TGF-?), tumor necrosis factor (TNF-a), insulin like growth factors (IGFs), and heparin-binding like epidermal growth factor (HB-EGF). As a consequence of this activity, high levels of certain MMPs might potentiate growth factor availability to renal tissues. Unfortunately, a connection between MMP activity and growth factor/cytokine action in diabetic kidney disease is currently lacking. The predictive value of microalbuminuria for the progression to overt nephropathy is not precise. This is clearly suggested by patients in whom urinary albumin excretion (UAE) is not increased; yet they nonetheless develop advanced renal lesions. Thus, a better understanding of the underlying pathogenesis of diabetic nephropathy is necessary in order to develop strategies to detect nephropathy at an earlier stage and also to develop and implement more target molecule-specific therapies. Results of the Diabetes Control and Complications Trial (DCCT have demonstrated that among intensively treated diabetic patients, tight glycemic control over a 7-year study period, as evidenced by an average HbA1c of < 7.0%, reduced the adjusted mean risk of albuminuria by 56% and reduced the risk of microalbuminuria by 43%. These results serve as confirmation that a major risk factor for the development of diabetic nephropathy is chronic hyperglycemia. Moreover, the DCCT demonstrated that long-term improvements in glycemic control could interrupt the progression of renal pathology. Based upon results of the DCCT, as well as emerging evidence in animal models of the importance of hyperglycemia-mediated dysregulation of MMP secretion and action in renal pathology, we hypothesize that 1) glucose homeostasis is directly involved in the regulation of the MMP system in humans; 2) as a consequence of chronic hyperglycemia, dysregulation of MMP activity in the kidney contributes to the onset and progression of diabetic nephropathy; and 3) clinically detectible abnormalities in MMP concentrations will herald the onset of diabetic nephropathy, indicating that MMP analysis may be a useful biomarker of diabetic nephropathy.