Role of renal crystal deposition in the progression of polycystic kidney disease

肾晶体沉积在多囊肾病进展中的作用

• 批准号: 436243303
• 负责人: Sebastian Strubl
• 金额: --
• 依托单位: Department of Molecular, Cellular, and Developmental Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/436243303?language=en
• 关键词: Role; renal; crystal; deposition; progression

Autosomal-dominant polycystic kidney disease (ADPKD) is a common and inherited disease with a frequency of 1:500 in world’s population. The disease progresses slowly to renal failure, typically in the 4-6th decades of life. For unknown reasons the rate of progression varies from patient to patient even within the same family suggesting that environmental factors may influence disease progression. Recent results from animal studies suggest that renal insults are required – in addition to the gene mutation – for renal cysts to develop. But rare forms of renal injury seem unlikely to trigger the constant disease progression in humans.Recent results of the Weimbs Laboratory suggest that a much more prevalent form of subclinical renal insult is the trigger of renal cyst formation that determines the rate of progression in ADPKD: microcrystals that are sporadically lodged in renal tubule lumens. They show that deposition of calcium oxalate (CaOx) crystals in renal tubules lead to rapid activation of the mTOR and Src/STAT3 signaling pathways, which are both strongly activated in ADPKD, too. Additionally, CaOx crystal deposition leads to rapid tubule diameter widening that can be blocked by mTOR inhibition. These results indicate that tubule dilation is a purposeful, and previously unrecognized, protective mechanism that facilitates crystal excretion. After crystal clearance, tubule diameters normalize within a week. However, in mice lacking PC1 – the protein affected in ADPKD – CaOx challenge leads to persistent tubule dilation that “overshoots” to cystic progression. This suggests that PC1 is required for a return to normal tubule diameters after insults. We hypothesize (1) that tubule dilation is an innate renal protective mechanism against tubular crystals and (2) that this mechanism acts as a trigger for tubule dilation leading to cyst formation in ADPKD. If correct - these findings immediately open a new and highly feasible avenue for therapeutic intervention because well-established treatments for recurring nephrolithiasis (dietary changes, increased water intake, citrate) should also be effective in slowing the progression of ADPKD.Using mouse and rat models of CaOx nephrolithiasis we will investigate tubule dilation and signaling pathway activation in response to crystal deposition and test whether citrate treatment prevents these effects (Aim 1). Using pharmacological inhibitors and genetic mouse models we will determine if tubule dilation is required for effective crystal clearance (Aim 2). Using conditional knockout mice for the ablation of cilia or PC1, we will investigate if tubule crystal deposition acts as a trigger for cystogenesis (Aim 3). Using a mosaic PC1-KO mouse model and a rat model of PKD we will determine if crystal burden modulates disease severity in PKD.

常染色体显性遗传性多囊肾病(ADPKD)是一种常见的遗传性疾病，在世界人口中的发病率为1：500。这种疾病进展缓慢，通常在生命的4-60年内发展为肾功能衰竭。由于未知的原因，病情进展的速度因患者而异，甚至在同一个家庭中也是如此，这表明环境因素可能会影响疾病的进展。最近的动物研究结果表明，除了基因突变外，肾脏的侮辱也是肾囊肿形成的必要条件。但罕见的肾损伤似乎不太可能触发人类疾病的持续进展。Weimbs实验室的最新结果表明，一种更普遍的亚临床肾损伤形式是肾囊肿形成的触发因素，这决定了ADPKD的进展速度：微晶体零星地滞留在肾小管腔内。他们发现，草酸钙(CaOx)晶体沉积在肾小管中导致mTOR和Src/STAT3信号通路的快速激活，这两个信号通路在ADPKD中也被强烈激活。此外，CaOx晶体沉积导致小管直径迅速扩大，这可以通过mTOR抑制来阻止。这些结果表明，小管扩张是一种有目的的、以前未被认识到的促进晶体排泄的保护性机制。晶体清除后，肾小管直径在一周内恢复正常。然而，在缺乏PC1的小鼠中，ADPKD-CaOx挑战中受影响的蛋白质会导致持续的小管扩张，从而“过度”导致囊性进展。这表明PC1是在侮辱后恢复正常肾小管直径所必需的。我们假设(1)肾小管扩张是肾脏对肾小管结晶的一种先天保护机制，(2)该机制是肾小管扩张导致ADPKD囊性形成的触发因素。如果正确-这些发现立即为治疗干预开辟了一条新的、高度可行的途径，因为成熟的复发性肾结石治疗方法(改变饮食、增加水分摄入、柠檬酸盐)应该也在减缓ADPKD的进展方面有效。利用CaOx肾结石的小鼠和大鼠模型，我们将研究晶体沉积对小管扩张和信号通路激活的反应，并测试柠檬酸盐治疗是否可以防止这些影响(目标1)。使用药物抑制剂和遗传小鼠模型，我们将确定有效的晶体清除是否需要小管扩张(目标2)。使用条件性基因敲除小鼠切除纤毛或PC1，我们将调查小管晶体沉积是否作为膀胱发生的触发因素(目标3)。使用嵌合型PC1-KO小鼠模型和PKD大鼠模型，我们将确定晶体负荷是否调节PKD的疾病严重程度。