RENAL INJURY AND ADAPTATION TO HEME PROTEINS

血红素加氧酶(HO)是机体代谢的限速酶。 亚铁血红素的降解。因此，HO降低了细胞内的血红素水平，a 促氧化剂，并最终获得抗氧化剂胆红素。HO 以氧化剂和细胞因子诱导的亚型HO-1和AN的形式存在 无反应的本构异构体HO-2，我们证明 HO-1的诱导对血红素氧化损伤的保护作用 蛋白质和其他毒素。HO-1的这些影响是偶然的 铁蛋白(细胞内主要铁结合蛋白)的合成 蛋白质)，并可能诱导血红素结合蛋白23(AN 可诱导的高亲和力血红素结合蛋白)； 反应限制氧化剂和细胞因子的细胞毒性 因为细胞内的血红素蛋白不稳定，血红素被释放。 我们最近观察到HO-1在肾脏中表达上调 发炎，并降低对后续侮辱的敏感性。那 HO-1参与炎症，是组织中的一个决定因素 因此，损伤使这种酶超越了有毒的肾病，进入了 具有及时和深远的生物吸引力的地区。我们建议4个 明确的目标。第一个具体目标是发展 在全球范围内过度表达HO-1和铁蛋白的转基因模型 在肾脏中也是如此；这种方法补充了 药理学研究。我们将测试这样的动物是否较少 容易受到有毒和煽动性的侮辱，我们有 获得了HO-1和铁蛋白具有保护作用的证据。这个 第二个特定目标将检查HO-1及其同源基因的诱导 作为抗氧化剂伤害的决定因素的分子。氧化剂 损伤是一种常见的有毒和 炎症状态，我们将分析其功能意义。 这种诱导处于抵抗氧化损伤的状态。第三 具体目的将考察其作用机制和意义。 我们在肾小管中观察到HO-1的诱导 急性肾小球炎症、肾毒性血清性肾炎； 这种依赖肿瘤坏死因子α的模型HO-1在小管和 保护肾脏免受损伤。第四个具体目标将审查 血管内皮细胞HO-1的诱导机制及意义 急性间质性炎症中的巨噬细胞。巨噬细胞 一般肾损伤和同种异体移植肾损伤的关键成分 尤其是拒绝。在我们特征性的急性同种异体移植模型中 我们将探讨拒绝的机制和意义 HO-1在间质巨噬细胞中的诱导我们的建议 因此，应用程序继续追求HO-1的功能，因为它 利用了一种新的策略，转基因小鼠，因为它定义了一种新的 受累区域即肾脏炎症。

Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme. HO thus reduces cellular levels of heme, a pro-oxidant, and ultimately procures bilirubin, an antioxidant. HO exists as an oxidant and cytokine-inducible isoform, HO-1, and an unresponsive constitutive isoform, HO-2, We demonstrate that induction of HO-1 protects against oxidant injury imposed by heme proteins and other toxins. These effects of HO-1 are contingent upon synthesis of ferritin (the major intracellular iron-binding protein), and possibly, induction of Heme Binding Protein 23 (an inducible high affinity heme binding protein); this integrated response limits the cytotoxicity of oxidants and cytokines incurred as intracellular heme proteins are destabilized and heme is released. We recently observed that HO-1 is upregulated in renal inflammation and reduces susceptibility to subsequent insults. That HO-1 is involved in inflammation and is a determinant if tissue injury thus carries this enzyme beyond toxic nephropathies into areas with timely and far-reaching biologic appeal. We propose 4 specific aims. The first specific aim is the development of transgrenic models that overexpress HO-1 and ferritin, globally, as well as regionally in the kidney; this approach complements pharmacologic studies. We will test whether such animals are less susceptible to toxic and inflammatory insults wherein we have obtained evidence for a protective role for HO-1 and ferritin. The second specific aim will examine induction of HO-1 and its allied molecules as determinants of resistance to oxidant injury. Oxidant injury represents a critical mechanism common to toxic and inflammatory states, and we will analyze functional significance of such induction in states of resistance to oxidative injury. The third specific aim will examine the mechanisms and significance underlying the induction of HO-1 we have observed in renal tubules in acute glomerular inflammation, nephrotoxic serum nephritis; in this TNFalpha-dependent model, HO-1 is induced in tubules and protects against renal injury. The fourth specific aim will examine the mechanisms and significance of induction of HO-1 in macrophages in acute interstitial inflammation. Macrophages are critical components in renal injury in general and in allograft rejection in particular. In our characterized model of acute allograft rejection we will pursue the mechanisms and significance of induction of HO-1 in interstitial macrophages. Our proposed application thus continues to pursue the functionality of HO-1, as it utilized a new strategy, transgenic mice, and as it defines a new area of involvement namely, renal inflammation.