Crystal Associated Renal Inflammation and Treatment Options

描述（由申请人提供）：草酸钙（CaOx）晶体是大多数泌尿系统结石的主要成分。它们也可沉积在原发性或肠源性高尿症患者的肾脏中。这些晶体可能具有肾毒性，引起炎症反应，导致纤维化、肾单位丢失和可能的肾衰竭。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），这似乎介导了许多细胞反应。CaOx晶体在大鼠肾脏中的沉积导致氧化应激，与肾素-血管紧张素系统（RAS）的激活相关，并增加大分子如骨桥蛋白（OPN）的产生，所述骨桥蛋白调节晶体形成及其在肾脏内的保留。间质性CaOx晶体沉积物被单核细胞和巨噬细胞包围。培养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）的产生增加相关。用抗氧化剂、自由基清除剂或血管紧张素受体阻断剂治疗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“肾结晶沉积通过激活肾素-血管紧张素系统和NADPH氧化酶以及产生活性氧来诱导肾脏炎症。ROS产生的减少将减少大分子如OPN和MCP-1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和体外通过将NRK 52 E和MDCK细胞暴露于CaOx晶体来严格测试这一假设，以确定将肾内晶体沉积和最终纤维化联系起来的精确分子事件系列。这些研究的结果将提高对肾钙质沉着症和肾结石中CaOx诱导的炎症的理解。研究可能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源性高尿酸相关的肾瘢痕形成。 公共卫生相关性： 草酸钙结晶沉积在肾脏中常见于原发性和肠源性高尿酸患者，引起肾损伤和炎症。继发于减肥手术的肠源性高尿症是一个严重的新出现的健康问题。我们建议通过将NRK 52 E和MDCK细胞培养物暴露于CaOx晶体并使用肾CaOx晶体沉积的大鼠模型来研究一系列连接肾内晶体沉积和最终纤维化的分子事件。这些研究的结果将提高对CaOx诱导的炎症的理解，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尿酸相关的肾瘢痕形成。

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.