The role of ICOSL in renal protection

项目摘要/摘要 肾小球损伤导致蛋白尿性肾脏疾病，通常进展为肾功能衰竭。尽管取得了进展，但 我们对肾小球疾病发病机制的认识，目前的治疗很大程度上依赖于 免疫抑制或抗高血压药物和特定的治疗方法仍然缺乏。不管是什么 潜在原因，肾小球损伤的一个早期和统一的事件是足细胞的形态变化 称为足突(FP)消失术。足细胞上αvβ3整合素的激活与早期病理有关 在几个肾小球中导致FP消失和随后诱导蛋白尿的过程 疾病，包括FSGS和糖尿病肾病。相反，阻断αvβ3的激活可显著减少蛋白尿 以及随后在FSGS和糖尿病肾病动物模型中的疾病进展。然而，目前还没有 临床成功的靶向αvβ3整合素的方法。 我们最近发现了可诱导型共刺激分子配体(ICOSL)在免疫保护中的新作用。 早期肾小球损伤(Koh等人，JCI，2019年)。肾小球ICOSL表达在肾小球疾病早期升高 人的FSGS和DN，随后在后期急剧下降。ICOSL缺乏的动物更多 易发生肾脏损伤和严重蛋白尿，可通过注射重组ICOSL抢救。 ICOSL的RGD基序对于与激活的αvβ3结合及其保护功能至关重要。尽管 ICOSL有助于肾脏保护的这一重要发现，更详细的机制研究是 要充分了解ICOSL作为αvβ3整合素的调节因子的肾脏保护行为，以及 开发有针对性的疗法。 根据我们已发表的和初步的数据，我们假设ICOSL表达增加是一种 足细胞作为内源性防御反应启动的机制，通过以下方式限制进行性肾损伤 抵消αvβ3整合素有害的过度激活。为了验证这一假设，我们将准确地 确定ICOSL表达的基本时间和空间调节，以部署其保护性 行动(目标1)，确定ICOSL如何实现肾脏保护(目标2)，并探索其治疗潜力 (目标3)。我们的研究将是迈向成功开发特定小说的关键步骤 αvβ3整合素介导的肾小球疾病的治疗。

Project Summary/Abstract Glomerular injury leads to proteinuric kidney diseases that often progress to renal failure. Despite advances in our understanding of the pathogenesis of glomerular disease, current treatment relies heavily on immunosuppressive or anti-hypertensive drugs and specific treatments are still lacking. Regardless of the underlying cause, one early and unifying event in glomerular injury is a morphological change in podocytes called foot process (FP) effacement. Activation of αvβ3 integrin on podocytes is linked to early pathological processes leading to FP effacement and the subsequent induction of proteinuria in several glomerular diseases, including FSGS and DN. Conversely, blocking of αvβ3 activation significantly reduces proteinuria and subsequent disease progression in animal models of FSGS and DN. However, there is currently no clinically successful approach designed to target αvβ3 integrin. We recently discovered a novel role for inducible co-stimulator ligand (ICOSL) in the protection against early glomerular injury (Koh et al., JCI, 2019). Glomerular ICOSL expression increases in early stages of human FSGS and DN, followed by a drastic decline at later stages. ICOSL deficient animals are more susceptible to kidney injury and severe proteinuria, and can be rescued by recombinant ICOSL injection. ICOSL’s RGD motif is critically important for binding to activated αvβ3 as well as its protective function. Despite this important discovery that ICOSL contributes to kidney protection, more detailed mechanistic studies are necessary to fully understand the renoprotective behavior of ICOSL as a regulator of αvβ3 integrin and to develop targeted therapies. Based on our published and preliminary data, we hypothesize that elevated ICOSL expression is a mechanism launched by podocytes as an endogenous defensive response to limit progressive kidney injury by counterbalancing the harmfully excessive activation of αvβ3 integrin. To test this hypothesis, we will precisely define the essential temporal and spatial regulation of ICOSL expression necessary to deploy its protective action (Aim 1), determine how ICOSL achieves renoprotection (Aim 2), and explore its therapeutic potential (Aim 3). Our studies will be essential steps in moving toward successful development of novel specific therapeutics for αvβ3 integrin-mediated glomerular diseases.