The Role of Wheat-Gluten in Polycystic Kidney Disease

小麦麸质在多囊肾病中的作用

基本信息

批准号：
10708139
负责人：
Takamitsu Saigusa
金额：
$ 29.69万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708139
关键词：
Acceleration Affect Amino Acids Animals Applications Grants Aspartate Attenuated Autosomal Dominant Polycystic Kidney Blood typing procedure Caseins Consumption Cyst Cystic Kidney Diseases Cystic kidney Cytoprotection Data Development Diet Dietary Proteins Disease Progression Disease model Elements Environmental Risk Factor Epithelial Cells Family Gene Mutation Genetic Gluconeogenesis Glutamates Gluten Growth Immune response Impairment Infection Infiltration Injury Intervention Kidney Kidney Diseases Knock-out Knockout Mice Liquid substance Lysine Macrophage Meat Mediating Metabolic Pathway Mitochondria Mus Mutation Oral Organelles Outcome Oxygen Consumption PKD1 gene PKD2 gene Pathway interactions Patients Phosphoenolpyruvate Plants Play Polycystic Kidney Diseases Post-Translational Protein Processing Production Proteins Reducing diet Renal function Renal tubule structure Rodent Role Saline Severity of illness Sorting Soy Proteins Stimulant Supplementation Testing Tubular formation Tyrosine Wheat amino acid metabolism cell injury chemokine clinically significant cytokine dietary restriction fighting functional disability glucose metabolism improved kidney cell mitochondrial dysfunction mutant non-genetic pre-clinical preclinical study recruit renal epithelium

项目摘要

Autosomal dominant polycystic kidney disease (ADPKD), is caused by mutations in PKD1 or PKD2 genes. Disease severity is highly variable, even among families with the same PKD gene mutation. This variability has been attributed, in part, to environmental factors. Among them, a high protein diet is one of the most recognized ADPKD progression-accelerating factor. Protein composition is also a key element that can affect the rate of cyst growth. For example, soy protein compared to casein (animal-based protein) diet slows kidney cyst in rodent PKD models. Our preclinical data shows that wheat gluten (WG) diet compared to casein protein diet decreased the number of kidney macrophages (MФ), expression of Ccl2 (but not Csf1 or Ccl5) and slowed the rate of cyst growth in Pkd1-knockout mice. Therefore, animal-based protein load may have cystogenesis-promoting effects through augmentation of the cystogenesis-promoting Ccl2 pathway. Previous studies show that loss of Pkd1 increases Ccl2 in the renal tubules facilitating the recruitment of MФ, promoting kidney cyst growth and that these effects were attenuated in Ccl2-Pkd1 double knockout mice. We found that animal protein load impairs kidney mitochondrial function in Pkd1-knockout mice. When these mice were fed a WG diet enriched with top 3 amino acids abundant in casein compared to WG diet, there was increased number of kidney MФ and cyst growth compared to counterparts fed an isocaloric WG diet. This suggest that specific AAs in the casein diet promotes cyst growth. Furthermore, treatment with lysine (most abundant AA in casein compared to WG diet), but not aspartate (second abundant in casein) or glutamate (most abundant in WG), suppressed markers of mitochondrial function, impaired glucose metabolism, increased gluconeogenesis marker phosphoenolpyruvate (Pepck1) and increased tubular injury in Pkd1 mouse kidney cells. Oral lysine supplementation (1wk) in Pkd1 knockout mouse increased kidney cyst growth and levels of Pepck1 compared to counterparts given a saline. These data are well aligned with a major role kidneys play in AA metabolism through the mitochondria, an organelle that is functionally impaired by PKD mutations. Our overarching hypothesis is that specific AA(s) abundant in an animal protein-based diet exacerbate mitochondrial dysfunction, increase chemokine expression, MФ recruitment, and accelerate cystogenesis. Aim1 will test the hypothesis that high casein-protein diet impairs mitochondrial function, activates chemokine Ccl2 expression, increases kidney MФ accumulation, and promotes cyst growth; and deletion of Ccl2 in Pkd1-knockout mice have opposite effects. Aim2 will test the hypothesis that specific AA (lysine) abundant in an animal-based protein diet compared to a plant-based diet, leads to mitochondrial dysfunction, increased immune response and accelerated cyst growth. The clinical significance of this grant proposal is that patients with PKD could benefit from a plant-based protein diet and recent plant-based meat development has made dietary protein modification a feasible intervention that is safe and can have immediate impact for patients with ADPKD that require long-term treatment.

常染色体显性多囊肾病 (ADPKD) 是由 PKD1 或 PKD2 基因突变引起的，即使在具有相同 PKD 基因突变的家族中，这种差异也部分归因于环境因素。高蛋白饮食是最受认可的 ADPKD 进展加速因素之一。蛋白质组成也是影响囊肿生长速度的关键因素，例如，大豆蛋白与酪蛋白（动物蛋白）相比。我们的临床前数据显示，与酪蛋白饮食相比，小麦麸质 (WG) 饮食减少了肾脏巨噬细胞 (MФ) 的数量、Ccl2（但不是 Csf1 或 Ccl5）和 Ccl2 的表达。减慢了 Pkd1 敲除小鼠的囊肿生长速度，因此，基于动物的蛋白质负载可能通过增强促进囊肿发生的 Ccl2 途径而具有促进囊肿发生的作用。先前的研究表明，Pkd1 的缺失会增加肾小管中的 Ccl2，促进 MФ 的募集，促进肾囊肿的生长，并且这些影响在 Ccl2-Pkd1 双敲除小鼠中减弱。我们发现动物蛋白负荷会损害 Pkd1 中的肾线粒体功能。与 WG 饮食相比，当这些小鼠喂食富含酪蛋白中前 3 种氨基酸的 WG 饮食时，肾脏 MФ 数量增加，囊肿生长增加。与饲喂等热量 WG 饮食的配对相比，这表明酪蛋白饮食中的特定 AA 会促进囊肿生长。此外，用赖氨酸（与 WG 饮食相比，酪蛋白中最丰富的 AA）治疗，但不会促进天冬氨酸（酪蛋白中第二丰富的 AA）或谷氨酸。（WG 中最丰富）、线粒体功能标记物受到抑制、葡萄糖代谢受损、糖异生标记物磷酸烯醇丙酮酸 (Pepck1) 增加以及肾小管损伤增加与给予生理盐水的捐赠者相比，口服赖氨酸（1 周）可增加 Pkd1 敲除小鼠的肾囊肿生长和 Pepck1 水平。这些数据与肾脏通过线粒体（一种细胞器）在 AA 代谢中发挥的主要作用非常一致。我们的总体假设是，动物蛋白饮食中丰富的特定 AA 会加剧线粒体功能障碍，增加趋化因子表达，MФ。 Aim1 将验证高酪蛋白饮食会损害线粒体功能、激活趋化因子 Ccl2 表达、增加肾脏 MФ 积累并促进囊肿生长的假设；而在 Pkd1 敲除小鼠中删除 Ccl2 会产生相反的效果。将检验以下假设：与植物性饮食相比，动物性蛋白质饮食中富含的特定 AA（赖氨酸）会导致线粒体功能障碍、增强免疫反应并加速囊肿生长。这项拨款提案的临床意义在于，多囊肾患者可以从植物性蛋白质饮食中受益，而最近植物性肉类的开发使膳食蛋白质调整成为一种可行的干预措施，安全且可以对需要长期治疗的 ADPKD 患者产生立竿见影的影响。 - 长期治疗。