氨酸抑制会禁用pyruvate脱酶,并诱导近接管细胞的代谢功能障碍,导致profibrotic表型
bioRxiv : the preprint server for biology
|January 13, 2025
概括
氨酸抑制剂 (CNIs) 通过使酸盐脱酶失活,导致近端管细胞的代谢功能障碍,从而导致纤维化. 激活酸盐脱酶可以减轻这种CNI诱导的损伤.
科学领域:
- 腎臟病學 (nephrology) 是一種醫學專業.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 氨酸抑制剂 (CNIs) 是重要的免疫抑制剂,但会导致毒性和纤维化.
- 将氨酸抑制与纤维化联系在一起的确切机制尚未完全理解.
研究的目的:
- 阐明氨酸抑制导致纤维化的分子机制.
- 确定潜在的治疗点,以减轻CNI诱导的毒性.
主要方法:
- 在慢性CNI毒性小鼠模型中单核RNA测序.
- 在体外研究中使用了人类初级脏近道管的上皮细胞.
- 在细胞培养和体内活体中对酸盐脱酶的药理活性.
主要成果:
- CNI治疗增加了受伤的近道管细胞,与与新陈代谢,衰老和纤维化相关的基因表达改变.
- 中枢脏因子使酸盐脱酶失活,使线粒体功能受损,并在人类细胞中诱导衰老.
- 二乙酸,一种pyruvate脱酶激活剂,改善了小鼠的CNI诱导纤维化和转录性变化.
结论:
- 氨酸抑制通过关闭pyruvate dehydrogenase来破坏近道管细胞代谢.
- 这种新陈代谢功能障碍促进了亲纤维菌表型,导致纤维化.
- 向酸盐脱酶活性可能提供一种预防CNI诱导毒性的策略.
更多相关视频
09:40Isolation, Characterization, And High Throughput Extracellular Flux Analysis of Mouse Primary Renal Tubular Epithelial Cells
Published on: June 20, 2018
17.4K
08:46Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
9.7K
相关概念视频
Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
Renal Tubule and Collecting Duct
758
The renal tubule is divided into three parts: the proximal convoluted tubule (PCT), the Loop of Henle (LOH), and the distal convoluted tubule (DCT).
Proximal Convoluted Tubule (PCT):
The PCT is the initial segment of the renal tubule, extending from the Bowman's capsule that encloses the glomerulus. Its convoluted structure and microvilli-lined cells increase the surface area for reabsorption. The PCT reabsorbs glucose, amino acids, sodium, and water from the filtrate, ensuring essential...
Proximal Convoluted Tubule (PCT):
The PCT is the initial segment of the renal tubule, extending from the Bowman's capsule that encloses the glomerulus. Its convoluted structure and microvilli-lined cells increase the surface area for reabsorption. The PCT reabsorbs glucose, amino acids, sodium, and water from the filtrate, ensuring essential...
758
GPCR Desensitization
5.8K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
5.8K
Nephrons
2.1K
The kidneys are intricate organs with millions of working units known as nephrons. Each nephron features two major structures: the renal corpuscle, which facilitates blood plasma filtration, and the renal tubule, which handles the glomerular filtrate. Blood supply is directly linked to the nephrons. The renal corpuscle consists of the glomerulus, a capillary network, and the Bowman's capsule, a double-walled epithelial structure that encases the glomerulus. The filtering of blood plasma...
2.1K
Chronic Pancreatitis I: Introduction
71
The pancreas, an elongated and flat gland situated behind the stomach, serves a vital function in digesting food and managing blood sugar levels.
Pancreatitis is the inflammation of the pancreas, which occurs when the immune system becomes active and causes swelling, pain, and disruptions in organ function. Pancreatitis can manifest as either an acute or chronic condition.
Acute pancreatitis arises suddenly and lasts for a brief duration, while chronic pancreatitis is a long-term affliction...
Pancreatitis is the inflammation of the pancreas, which occurs when the immune system becomes active and causes swelling, pain, and disruptions in organ function. Pancreatitis can manifest as either an acute or chronic condition.
Acute pancreatitis arises suddenly and lasts for a brief duration, while chronic pancreatitis is a long-term affliction...
71
Feedback Inhibition
53.6K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
53.6K
