Treatment of Kidney Disease in Diabetes and Obesity

描述(申请人提供)：肥胖和糖尿病是美国心血管和肾脏疾病的主要原因。这一点越来越令人担忧，因为肥胖症和胰岛素抵抗的发生率正在增加，预计到2030年，多达四分之一的美国人将患有糖尿病。尽管对糖尿病患者实施了所有有益的干预措施，包括严格的血糖控制、严格的血压控制、血管紧张素转换酶抑制或血管紧张素II受体拮抗剂，但大多数患者的肾脏疾病仍在发展。因此，迫切需要更多的治疗方式来调节肥胖和糖尿病肾病的发病途径，以减缓肥胖和糖尿病患者的肾脏疾病的进展。我们实验室的研究表明，用高活性和特异性的TGR5激动剂治疗糖尿病小鼠可以防止糖尿病肾病的进展。TGR5激活的有益效果与雌激素相关受体�(ERR�)和sirtuin3(SIRT3)的刺激有关。在这个方案中，我们将检验假设：1)TGR5在糖尿病和肥胖的肾脏疾病的调节中起重要作用；2)TGR5抑制加速，TGR5激活防止肥胖和糖尿病肾脏疾病；3)TGR5的有益作用部分通过刺激ERR�介导。在特定目标1中，我们将确定肾脏特异性TGR5缺失在肥胖和糖尿病肾病中的作用。在特定目标2中，我们将确定肾脏特异性TGR5过度表达在肥胖和糖尿病肾脏疾病中的作用。在具体目标3中，我们将确定TGR5对肥胖和糖尿病肾脏疾病的调节作用是否依赖于肾脏特异性ERR�的激活。影响：TGR5和ERR�在调节肥胖和糖尿病肾脏疾病中的潜在作用是非常新颖的，将对肥胖和糖尿病相关肾脏并发症的治疗具有重大意义。TGR5和ERR�在调节线粒体生物发生、能量代谢和能量消耗方面具有不同的作用：因此，它们与其他用于治疗糖尿病及其并发症的干预措施截然不同，在其他干预措施中，TGR5还可以诱导体重减轻和预防肥胖。

DESCRIPTION (provided by applicant): Obesity and diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. This is of increasing concern since the incidence of obesity and insulin resistance is increasing and as many as 1 in 4 Americans are expected to have diabetes by the year 2030. In spite of all the beneficial interventions implemented in patients with diabetes, including tight glucose control, tight blood pressure control, angiotensin converting enzyme inhibition or angiotensin II receptor antagonism, renal disease progresses in most of these patients. Additional treatment modalities that modulate the pathogenesis pathways involved in obesity and diabetic nephropathy are therefore urgently needed to slow the progression of renal disease in patients with obesity and diabetes. Studies from our laboratory indicate that treatment of diabetic mice with a highly active and specific TGR5 agonist prevents the progression of diabetic nephropathy. The beneficial effects of TGR5 activation are associated with stimulation of estrogen-related receptor � (ERR�) and sirtuin 3 (SIRT3). In this proposal we will test the hypotheses that: 1) TGR5 plays an important role in modulation of kidney disease in diabetes and obesity; 2) TGR5 inhibition accelerates and TGR5 activation prevents obesity and diabetic kidney disease; 3) the beneficial effects of TGR5 are mediated in part through stimulation of ERR�. In Specific Aim 1 we will determine the effects of kidney specific TGR5 deletion in kidney disease in obesity and diabetes. In Specific Aim 2 we will determine the effects of kidney specific TGR5 overexpression in kidney disease in obesity and diabetes. In Specific Aim 3 we will determine whether the effect of TGR5 in modulation of kidney disease in obesity and diabetes is dependent on kidney specific ERR� activation. Impact: The potential role of TGR5 and ERR� in modulating obesity and diabetic renal disease is very novel and will have major implications for the treatment of obesity and diabetes related renal complications. TGR5 and ERR� have distinct actions of regulating mitochondrial biogenesis, energy metabolism and energy expenditure: they are therefore quite distinct from other interventions used in treatment of diabetes and its complications where TGR5 can also induce weight loss and prevent obesity.