Mechanism of Renal Lipotoxicity in Obesity and Diabetes

肥胖和糖尿病肾脂毒性机制

• 批准号: 8734718
• 负责人: Jesus H. Dominguez
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734718
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Acute-Phase Proteins; Address; Adult; Allogenic; Amyloid; Animal Model; Animals; Autologous Transplantation; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Chronic; Chronic Kidney Failure; Clinical; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease model; Embryo; Employee Strikes; End stage renal failure; Engraftment; Face; Future; General Population; Goals; Harvest; Immunosuppression; In Vitro; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Laboratories; Mediating; Minority; Modeling; Natural regeneration; Nephrology; Obesity; Organ; Pain; Patients; Population; Prevention; Proteins; Protocols documentation; Rattus; Recovery; Regenerative Medicine; Renal function; Renal tubule structure; Research; Serum; Serum Proteins; Serum amyloid A protein; Source; Stem cell transplant; Stem cells; Structure; Testing; Translations; Transplantation; Tubular formation; Veterans; Work; base; clinically relevant; diabetic patient; experience; high risk; improved; innovation; kidney cell; novel; public health relevance; regenerative; renal ischemia; research study; therapy development; tool; translational study

DESCRIPTION (provided by applicant): Progressive chronic kidney disease (CKD) particularly that due to diabetes, is a global problem that causes untold suffering in Veterans and the general population. Diabetic patients are at high risk of CKD and many face the prospect of irrevocable renal decline to end stage renal disease (ESRD). For some, renal transplantation is an effective way to treat ESRD, however, only a small minority receives a kidney. The majority of ESRD patients remain on dialysis, and most patients ultimately succumb to painful complications. One promising approach to CKD-ESRD is regenerative nephrology, and attempts have been made to restore renal function in animal models with stem cells. However, transplantation of stem cells from diverse sources has not yet fulfilled the basic postulates of cytotherapy: engraftment, differentiation and expansion. We devised a completely different strategy for renal regeneration by cell transplantation in CKD, and accomplished long-term kidney cell engraftment and successful renal regeneration with allogeneic transplants and autotransplants of adult primary kidney cells that express the tubulogenic protein Serum Amyloid A1 (SAA). This proposal aims to test the novel and clinically relevant hypothesis that transplantation with renal tubule cells expressing the tubulogenic protein serum amyloid A (SAA) rescues kidney function in experimental CKD. Furthermore, we propose that cells from kidneys with CKD can be expanded in vitro and then auto-transplanted to effect recovery of both renal structure and function non-invasively. These studies are a necessary prelude to future clinical translation in which part of one kidney would be removed, its tubules harvested and transfected and the derived tubular cells returned to the donor to restore renal function without need for immune suppression. The proposed work is derived from accumulated experience: First, we found that the acute phase protein SAA is critical in tubulogenesis in the embryo and during renal regeneration after ischemia (Kelly et al Am J Physiol 296: F1355, 2009). Second, immortalized renal tubule (NRK52E) cells reprogrammed with SAA and administered intravenously produce striking improvements in renal function in multiple models of acute kidney injury (Kelly et al Am J Physiol 299: F453, 2010). Third, transplantation with primary renal tubule cells resulted in significant recovery of structure and function in both chronic and acute kidney disease (Kelly et al Am J Physiol 303:F357, 2012). We already have conducted extensive experiments and found that CKD can be corrected in six rats with cells from a single donor of the same strain. Our hypothesis has generated the following specific aims: (1) To evaluate cytotherapy, including autotransplantation, as novel treatment for CKD in diabetic nephropathy and ischemia. (2) To determine the mechanisms by which cytotherapy with SAA expressing primary renal tubule cells restores renal function in CKD from diabetic nephropathy and ischemia. The proposed innovative, translational study will define mechanisms of renal regeneration, potentially extend the utility of organs available for transplantation, and develop means for autotransplantation. We suggest that further defining mechanisms of cytotherapy-mediated renal regeneration and improvement in kidney function, including cell grafting effects, will stimulate further research on regeneration and facilitate the development of therapies to target the specific mechanisms identified. The ultimate goal is the prevention and treatment of CKD in Veterans and the general population.

描述（由申请人提供）： 进行性慢性肾病（CKD），特别是由糖尿病引起的肾病，是一个全球性问题，给退伍军人和普通民众带来了难以言表的痛苦。糖尿病患者患 CKD 的风险很高，许多人面临不可逆转的肾功能衰退至终末期肾病 (ESRD) 的前景。对于一些人来说，肾移植是治疗 ESRD 的有效方法，但只有极少数人接受了肾脏移植。大多数终末期肾病患者仍接受透析，大多数患者最终死于痛苦的并发症。再生肾病学是治疗 CKD-ESRD 的一种有前景的方法，人们已经尝试用干细胞在动物模型中恢复肾功能。然而，不同来源的干细胞移植尚未满足细胞疗法的基本假设：植入、分化和扩增。 我们设计了一种完全不同的通过细胞移植治疗 CKD 肾再生的策略，并通过表达肾小管生成蛋白血清淀粉样蛋白 A1 (SAA) 的成体原代肾细胞的同种异体移植和自体移植实现了长期肾细胞植入和成功的肾再生。该提案旨在测试新的临床相关假设，即移植表达肾小管生成蛋白血清淀粉样蛋白 A (SAA) 的肾小管细胞可挽救实验性 CKD 中的肾功能。此外，我们建议来自 CKD 肾脏的细胞可以在体外扩增，然后进行自体移植，以非侵入性地恢复肾脏结构和功能。这些研究是未来临床转化的必要前奏，在未来的临床转化中，将切除一个肾脏的一部分，收获并转染其肾小管，并将衍生的肾小管细胞返回供体以恢复肾功能，而无需免疫抑制。所提出的工作源自积累的经验：首先，我们发现急性期蛋白 SAA 在胚胎肾小管发生和缺血后肾再生过程中至关重要（Kelly 等人 Am J Physiol 296：F1355，2009）。其次，用 SAA 重新编程并静脉注射的永生化肾小管 (NRK52E) 细胞在多种急性肾损伤模型中显着改善肾功能 (Kelly 等人 Am J Physiol 299: F453, 2010)。第三，原代肾小管细胞移植导致慢性和急性肾病的结构和功能显着恢复（Kelly等人Am J Physiol 303：F357，2012）。我们已经进行了广泛的实验，发现使用来自同一品系的单个供体的细胞可以纠正六只大鼠的 CKD。我们的假设产生了以下具体目标：（1）评估细胞疗法（包括自体移植）作为糖尿病肾病和缺血性 CKD 的新型治疗方法。 (2) 确定表达SAA的原代肾小管细胞的细胞疗法恢复糖尿病肾病和缺血性CKD肾功能的机制。拟议的创新转化研究将定义肾脏再生的机制，有可能扩展可用于移植的器官的效用，并开发自体移植的方法。我们建议，进一步明确细胞疗法介导的肾再生和肾功能改善的机制，包括细胞移植效应，将刺激再生研究的进一步发展，并促进肾功能的改善。 针对已确定的特定机制开发治疗方法。最终目标是预防和治疗退伍军人和普通人群的 CKD。