Response Of Renal Cells To Osmotic Stress

肾细胞对渗透压的反应

• 批准号: 7321555
• 负责人: MAURICE BENJAM BURG
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7321555
• 关键词: Response; Renal; Cells; Osmotic; Stress

The osmolality of the blood in the renal inner medulla is high and varies with the urinary concentration. Both NaCl and urea are elevated. The medullary cells evidently survive and function in this adverse environment. The ongoing studies are concerned with understanding the mechanisms involved. When cells are stressed by a high salt environment, they generally accumulate osmotically active organic solutes ("osmolytes") in order to maintain a favorable internal milieu, while regulating their volume. We identified the organic osmolytes in renal inner medullary cells as glycerophosphocholine (GPC), betaine, sorbitol, taurine, and inositol, and showed that the osmolyte levels varied with urine concentration (and, presumably, medullary salt and urea concentrations). We are now using renal cell cultures and living animals to study the mechanism and control of osmoregulatory accumulation of these organic osmolytes, including the transcription factor (TonEBP/OREBP) that is involved. High NaCl signals activation of TonEBP via PKA, ATM, PARP-1, HSP90, PI3K and other systems. In addition, the acute response to high osmolality may include cell cycle arrest and apoptosis in proliferating cultures of renal medullary cells. High NaCl causes DNA damage in cell culture, while high urea causes both DNA (8-oxoguanine lesions) and protein(cabonylation) damage. Both the DNA damage and protein carbonylation are present in normal renal inner medullas. The DNA damage is rapidly repaired in vivo when renal inner medullary osmolality is reduced by the diuretic, furosemide. We are studying the mechanisms involved, including the role of p53, p38, Ku86, and GADD proteins.

肾内髓质血液渗透压高，随尿浓度变化。NaCl和尿素均升高。髓质细胞显然能在这种不利的环境中存活并发挥功能。正在进行的研究关注于了解所涉及的机制。当细胞受到高盐环境的压力时，它们通常会积累具有渗透活性的有机溶质（“渗透物”），以维持有利的内部环境，同时调节其体积。我们确定肾髓内细胞中的有机渗透物为甘油酰胆碱（GPC）、甜菜碱、山梨醇、牛磺酸和肌醇，并表明渗透物水平随尿浓度（可能还有髓盐和尿素浓度）而变化。我们现在正在利用肾细胞培养和活体动物研究这些有机渗透物的渗透调节积累的机制和控制，包括参与的转录因子（TonEBP/OREBP）。高NaCl信号通过PKA、ATM、PARP-1、HSP90、PI3K等系统激活TonEBP。此外，对高渗透压的急性反应可能包括肾髓细胞增殖培养中的细胞周期阻滞和细胞凋亡。在细胞培养中，高NaCl会导致DNA损伤，而高尿素会导致DNA（8-氧鸟嘌呤损伤）和蛋白质（cabonylation）损伤。正常肾内髓均存在DNA损伤和蛋白质羰基化。当利尿剂速尿降低肾髓内渗透压时，DNA损伤在体内迅速修复。我们正在研究其中的机制，包括p53、p38、Ku86和GADD蛋白的作用。