COMPENSATORY HYPERTROPHY OF THE KIDNEY

肾脏代偿性肥大

• 批准号: 3232429
• 负责人: LEON G FINE
• 金额: $ 15.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3232429
• 关键词: amiloride; antiport; apical membrane; disease /disorder model; hormone regulation /control mechanism; insulin; kidney cell; kidney hypertrophy; laboratory rabbit; membrane potentials; mitogens; prostaglandin E; receptor; sodium chloride

The purpose of the proposed studies is to establish an in vitro model of renal tubular hypertrophy and to examine whether a unifying mechanism can be found for the initiation of cell hypertrophy. Prior studies have suggested that a flow-induced increase in luminal Na-H antiport occurs in the proximal tubules of kidneys with reduced nephron populations and it is possible that this signal (either Na influx or intracellular alkalization) initiates the process of cell growth. Many mitogens stimulate cell proliferation by inducing an early increase in Na-H antiport. A primary culture of proximal tubular cells grown in serum-free hormone supplemented medium will be stimulated to hypertrophy by prolonged exposure to insulin, prostaglandin E1 and hypertonic sodium chloride. The existence of a luminal Na-H antiporter will be demonstrated by measuring Na influx kinetics and H+ efflux rates in intact cells. We will study the acute effects of the hypertrophic stimuli on these transport processes and the respective stimulatory and inhibitory effects of a transmembrane H+ gradient and amiloride, a competitive inhibitor, of the Na-H antiport. The steady-state rate of Na-H antiport will be studied in hypertrophied vs. non-hypertrophied cells and the ability of prolonged exposure to amiloride to inhibit the hypertrophic response will be evaluated. Our ability to induce hypertrophy without cell proliferation in this experimental model using a variety of completely different stimuli (i.e., hormonal and ionic) will make it possible to ascertain whether a single initiating event is common to the process of cell growth. If increased Na-H antiport is consistently found, it is likely that this could be the event which initiates hypertrophy of renal tubular cells in vivo.

本研究的目的是建立一种体外模型， 肾小管肥大，并检查是否有一个统一的机制， 是细胞肥大的起始点。 先前的研究 表明，流动诱导的增加，在管腔钠-H反向转运发生在 肾脏近端小管减少，肾单位数量减少， 可能该信号（钠内流或细胞内碱性化） 启动细胞生长的过程。 许多有丝分裂原刺激细胞 通过诱导Na-H反向转运的早期增加来抑制增殖。 主 培养在无血清激素补充的培养基中生长的近端肾小管细胞 培养基将通过长时间暴露于胰岛素而被刺激肥大， 前列腺素E1和高渗氯化钠。 的存在 腔钠-氢反向转运蛋白将通过测量钠内流来证明 动力学和完整细胞中的H+流出率。 我们将研究急性 肥大刺激对这些运输过程的影响， 跨膜H+的各自刺激和抑制作用 梯度和阿米洛利，一种竞争性抑制剂，钠-H反向转运。 的 将在肥大与肥大患者中研究稳态Na-H反向转运速率。 非肥大细胞和长期暴露于阿米洛利的能力 以抑制肥大反应。 的能力 在该实验模型中诱导肥大而无细胞增殖 使用各种完全不同的刺激（即，激素和离子） 将有可能确定是否有一个单一的启动事件， 细胞生长过程中常见的。 如果Na-H反向转运增加， 一致发现，这可能是事件， 在体内引发肾小管细胞肥大。