MATRIX METALLOPROTEINASES IN DIABETIC KIDNEY DISEASE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在1型DM患者中，约50%的有20年病史的患者发生糖尿病肾病。此外，糖尿病肾病是美国终末期肾病（ESRD）的最常见原因，占所有新诊断的ESRD病例的30-40%。在美国，糖尿病患者的ESRD相关费用估计为51，000美元/患者年。据估计，糖尿病肾衰竭患者每年的护理费用为30亿至40亿美元。总之，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经济影响。在发生肾功能不全的个体中，已经确定了发生肾病的几个风险因素，包括糖尿病持续时间、诊断时的年龄、种族、全身性或肾小球性高血压、血糖控制不良、肾病遗传易感性和饮食组成。然而，参与糖尿病肾病发生和发展的确切致病机制仍知之甚少。此外，没有统一的假设存在来解释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5阶段过程，从肾小球超滤和肾肥大的状况（第1阶段）进展到肾小球基底膜（GBM）增厚和系膜扩张（第2阶段），再到微量白蛋白尿和肾小球滤过率（GFR）的最终下降（第3阶段），至伴有重度高血压和中重度肾功能不全后遗症的明显蛋白尿（4期），至最终的ESRD（5期）。据推测，GBM厚度和含量的早期变化最终影响GBM的过滤特性，首先导致尿白蛋白排泄增加，并最终导致明显的蛋白尿。这些措施是我们唯一的临床检测指标的肾损害。由于肾脏中细胞外基质（ECM）降解的主要生理调节因子是基质金属蛋白酶（MMP），细胞外基质合成和降解的失衡可能导致ECM周转改变，这可能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，MMP活性可能下调，从而允许过量ECM沉积和系膜扩张。链脲佐菌素（STZ）治疗大鼠的研究支持了这一点，在这些大鼠中，MMP被抑制，肾组织中金属蛋白酶组织抑制剂（TIMP-1）增加。然而，来自人类研究的数据表明了一种更复杂的相互作用。例如，在2型DM中，微量白蛋白尿的发展可通过92 kDa MMP、MMP-9的血浆浓度的增加来预示，并且升高的MMP-9血清浓度与肾病的发作和进展相关。此外，MMP-9血清浓度与尿足细胞数量相关，尿足细胞数量是肾功能不全的早期标志物。虽然MMP活性的增加似乎违反直觉的疾病的发病机制，涉及增强ECM积累和疤痕，最近的数据表明，一个重要的行动MMPs，超越其对ECM重塑的直接影响，是释放或激活促纤维化细胞因子和生长因子，如转化生长因子-？(TGF-?),肿瘤坏死因子（TNF-α）、胰岛素样生长因子（IGF）和肝素结合样表皮生长因子（HB-EGF）。作为这种活性的结果，高水平的某些MMPs可能增强肾组织的生长因子可用性。不幸的是，MMP活性和生长因子/细胞因子在糖尿病肾病中的作用之间的联系目前缺乏。 微量白蛋白尿对进展为显性肾病的预测价值并不精确。尿白蛋白排泄（UAE）未增加的患者明确提示了这一点，但他们仍发生了晚期肾脏病变。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，在早期阶段检测肾病，并开发和实施更多的靶分子特异性治疗。糖尿病控制和并发症试验（DCCT）的结果表明，在强化治疗的糖尿病患者中，在7年的研究期内严格控制血糖，如平均HbA 1c <7.0%，可将白蛋白尿的校正平均风险降低56%，并将微量白蛋白尿的风险降低43%。这些结果证实了糖尿病肾病发展的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学的进展。基于DCCT的结果，以及在高血糖介导的MMP分泌和作用失调在肾脏病理学中的重要性的动物模型中出现的证据，我们假设1）葡萄糖稳态直接参与人类MMP系统的调节; 2）由于慢性高血糖症，肾脏中MMP活性的失调有助于糖尿病肾病的发生和发展;和3）临床上可检测到的MMP浓度的异常将预示糖尿病肾病的发作，表明MMP分析可能是糖尿病肾病的有用生物标志物。

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.