Crystal Associated Renal Inflammation and Treatment Options

描述（由申请人提供）：草酸钙 (CaOx) 晶体是大多数尿结石的主要成分。它们还沉积在原发性或肠道高草酸尿症患者的肾脏中。这些晶体可能具有肾毒性，引起炎症反应，导致纤维化、肾单位损失和可能的肾功能衰竭。组织培养研究表明晶体和肾细胞之间的相互作用产生活性氧（ROS），它似乎介导许多细胞反应。大鼠肾脏中的 CaOx 晶体沉积会导致氧化应激，与肾素-血管紧张素系统 (RAS) 的激活有关，并增加骨桥蛋白 (OPN) 等大分子的产生，从而调节晶体的形成及其在肾脏内的保留。间质 CaOx 晶体沉积物被单核细胞和巨噬细胞包围。培养中的肾上皮细胞暴露于 CaOx 和 CaP 晶体与趋化因子、单核细胞趋化蛋白 1 (MCP-1) 的产生增加有关。使用抗氧化剂、自由基清除剂或血管紧张素受体阻滞剂进行治疗可减少实验动物肾脏中的 CaOx 晶体沉积。基于这些结果，我们假设“肾晶体沉积通过激活肾素-血管紧张素系统和NADPH氧化酶以及活性氧的产生而诱发肾脏炎症。ROS产生的减少将减少OPN和MCP-1等大分子的合成，从而减少单核细胞和巨噬细胞向肾间质的迁移以及随后的炎症和纤维化。”我们建议使用肾 CaOx 晶体沉积的大鼠模型在体内严格测试这一假设，并通过将培养的 NRK52E 和 MDCK 细胞暴露于 CaOx 晶体来在体外严格测试这一假设，以便定义将肾内晶体沉积和最终纤维化联系起来的一系列精确的分子事件。此类研究的结果将提高对 CaOx 诱导的肾钙质沉着症和肾结石炎症的了解。研究可能提供新的治疗目标和更好的治疗选择，以预防与原发性和肠道高草酸尿症相关的肾脏疤痕。 公共卫生相关性： 原发性和肠性高草酸尿症患者常见草酸钙晶体沉积在肾脏，导致肾损伤和炎症。减肥手术继发的肠道高草酸尿症是一个严重的新出现的健康问题。我们提议通过将培养的 NRK52E 和 MDCK 细胞暴露于 CaOx 晶体并使用肾 CaOx 晶体沉积的大鼠模型来研究将肾内晶体沉积和最终纤维化联系起来的一系列分子事件。此类研究的结果将提高对 CaOx 诱导炎症的认识，并提供新的治疗靶点和更好的治疗选择，以预防与原发性和肠道高草酸尿症相关的肾脏疤痕形成。

DESCRIPTION (provided by applicant): Crystals of calcium oxalate (CaOx), are major constituents of most urinary stones. They are also seen deposited in the kidneys of patients with primary or enteric hyperoxaluria. These crystals can be nephrotoxic, evoke an inflammatory response leading to fibrosis, loss of nephrons and possible renal failure. Tissue culture studies indicate that interactions between the crystals and renal cells produce reactive oxygen species (ROS), which appear to mediate many of the cellular responses. CaOx crystal deposition in rat kidneys leads to oxidant stress, is associated with the activation of renin-angiotensin system (RAS), and increases in the production of macromolecules such as osteopontin (OPN) that modulate crystal formation and their retention within the kidneys. Interstitial CaOx Crystal deposits are surrounded by monocytes and macrophages. Exposure of renal epithelial cells in culture to CaOx and CaP crystals is associated with increased production of the chemokine, monocyte chemoattractant protein-1 (MCP-1). Treatments with anti-oxidants, free radical scavengers, or angiotensin receptor blockers reduce CaOx crystal deposition in the kidneys of experimental animals. Based on these results, we hypothesize that "Renal crystal deposition induces inflammation in kidneys via the activation of renin-angiotensin system and NADPH oxidase, and production of reactive oxygen species. Reduction in ROS production will reduce the synthesis of macromolecules such as OPN and MCP-1 thereby reducing migration of monocytes and macrophages into the renal interstitium and subsequent inflammation and fibrosis." We propose to rigorously test this hypothesis in vivo using a rat model of renal CaOx crystal deposition and in vitro by exposing NRK52E and MDCK cells in culture to CaOx crystals, in order to define the precise series of molecular events that link intrarenal crystal deposition and eventual fibrosis. Results of such studies will improve the understanding of CaOx induced inflammation in nephrocalcinosis and nephrolithiasis. Studies may provide novel treatment targets and better treatment options to prevent the renal scarring that is associated with primary and enteric hyperoxaluria. PUBLIC HEALTH RELEVANCE: Calcium oxalate crystal deposition in the kidneys is common in patients with primary and enteric hyperoxaluria, causing renal injury and inflammation. Enteric hyperoxaluria secondary to bariatric surgery is a serious emerging health problem. We are proposing to study the series of molecular events that link intrarenal crystal deposition and eventual fibrosis by exposing NRK52E and MDCK cells in culture to CaOx crystals and using a rat model of renal CaOx crystal deposition. Results of such studies will improve the understanding of CaOx induced inflammation and provide novel treatment targets and better treatment options to prevent the renal scarring that is associated with primary and enteric hyperoxaluria.