Crystal Associated Renal Inflammation and Treatment Options

描述（由申请人提供）：草酸钙晶体（CaOx）是大多数尿路结石的主要成分。它们也见于原发性或肠性高血氧症患者的肾脏中。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），它似乎介导了许多细胞反应。CaOx晶体沉积在大鼠肾脏导致氧化应激，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，这些大分子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。培养的肾上皮细胞暴露于CaOx和CaP晶体中，与趋化因子单核细胞趋化蛋白-1 （MCP-1）的产生增加有关。用抗氧化剂、自由基清除剂或血管紧张素受体阻滞剂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，从而减少随后的炎症和纤维化。”我们建议在体内使用大鼠肾CaOx晶体沉积模型严格验证这一假设，并在体外通过将培养的NRK52E和MDCK细胞暴露于CaOx晶体中，以确定连接肾内晶体沉积和最终纤维化的精确分子事件系列。这些研究结果将提高对CaOx在肾钙质沉着症和肾结石中引起的炎症的认识。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血氧血症相关的肾瘢痕形成。

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.