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Crystal Associated Renal Inflammation and Treatment Options

晶体相关的肾脏炎症和治疗选择

基本信息

批准号：
8223235
负责人：
SAEED R. KHAN
金额：
$ 31.23万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223235
关键词：
Angiotensin II Angiotensin Receptor Angiotensins Animal Model Animals Antioxidants Autopsy Binding Biopsy Blood Vessels Blood capillaries CD44 gene Calcium Oxalate Cell Line Cell physiology Cells Chemotactic Factors Childhood Chronic Kidney Failure Collagen Crystal Formation Deposition Development Down-Regulation Duct (organ) structure Electrons End stage renal failure Endothelium Enteral Environment Environmental Risk Factor Epithelial Epithelial Cells Epithelium Event Excision Excretory function Exposure to Fibrosis Free Radical Scavengers Gastrointestinal Diseases Generations Genetic Health Human Hyperoxaluria In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury Jejunoileal Bypass Kidney Kidney Calculi Kidney Failure Kidney Papilla Leukocytes Light Link Liquid substance Location MDCK cell Mediating Membrane Microscopic Modeling Molecular Monocyte Chemoattractant Protein-1 Myofibroblast NADH NADPH Oxidase Nephrocalcinosis Nephrolithiasis Nephrons Nephrotoxic Nuclear Operative Surgical Procedures Oxalates Oxidation-Reduction Oxidative Stress Pathogenesis Pathology Patients Peptidyl-Dipeptidase A Physiological Play Primary Hyperoxaluria Production Rattus Reactive Oxygen Species Regulation Renal tubule structure Renin Renin-Angiotensin System Role Secondary to Series Signal Transduction Superoxides Testing Transforming Growth Factors Tubular formation Urinary Calculi Vascular Permeabilities absorption animal tissue bariatric surgery base bikunin brushite calcification calcium phosphate capillary chemokine improved in vitro Model in vivo interstitial interstitial cell kidney cell killings macromolecule macrophage migration monocyte novel osteopontin oxidant stress prevent public health relevance renal scarring response tissue culture tissue repair tubular necrosis urinary

项目摘要

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.

描述(申请人提供)：草酸钙晶体(CaOx)，是大多数尿路结石的主要成分。它们也可以沉积在原发性或肠源性高草酸尿症患者的肾脏中。这些晶体可能是肾毒性的，引起炎症反应，导致纤维化、肾单位丢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会产生活性氧物种(ROS)，这似乎是许多细胞反应的中介。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)的激活有关，并增加了大分子如骨桥蛋白(OPN)的产生，这些大分子调节晶体的形成和它们在肾脏内的滞留。间质CaOx晶体沉积被单核细胞和巨噬细胞包围。培养的肾上皮细胞暴露在CaOx和CaOx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。抗氧化剂、自由基清除剂或血管紧张素受体阻滞剂的治疗减少了实验动物肾脏中CaOx晶体的沉积。基于这些结果，我们假设：“肾脏晶体沉积通过激活肾素-血管紧张素系统和NADPH氧化酶，并产生活性氧物种，导致肾脏炎症。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和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说，并在体外通过将培养中的NRK52E和MDCK细胞暴露于CaOx晶体来严格测试这一假说，以确定将肾内晶体沉积与最终纤维化联系起来的一系列精确的分子事件。这些研究的结果将提高对CaOx在肾钙化和肾结石中引起的炎症的理解。研究可能提供新的治疗靶点和更好的治疗选择，以防止与原发性和肠源性高草酸尿相关的肾脏瘢痕形成。公共卫生相关性：在原发性和肠源性高草酸尿症患者中，肾脏中草酸钙结晶沉积是常见的，导致肾脏损伤和炎症。减肥手术后继发的肠源性高草酸尿是一个严重的新出现的健康问题。我们建议通过将培养中的NRK52E和MDCK细胞暴露于CaOx晶体并使用大鼠肾脏CaOx晶体沉积的模型来研究肾内晶体沉积和最终纤维化之间的一系列分子事件。这些研究的结果将提高对CaOx引起的炎症的了解，并提供新的治疗目标和更好的治疗选择，以防止与原发性和肠源性高草酸尿相关的肾脏瘢痕形成。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations.

DOI：
10.1016/j.juro.2012.05.078
发表时间：
2013-03
期刊：
The Journal of urology
影响因子：
0
作者：
Khan SR
通讯作者：
Khan SR

Nephrocalcinosis in animal models with and without stones.

DOI：
10.1007/s00240-010-0303-4
发表时间：
2010-12
期刊：
Urological research
影响因子：
0
作者：
Khan SR
通讯作者：
Khan SR

An aqueous extract of Ammi visnaga fruits and its constituents khellin and visnagin prevent cell damage caused by oxalate in renal epithelial cells.

DOI：
10.1016/j.phymed.2009.10.011
发表时间：
2010-07
期刊：
PHYTOMEDICINE
影响因子：
7.9
作者：
Vanachayangkul, P.;Byer, K.;Khan, S.;Butterweck, V.
通讯作者：
Butterweck, V.

Kidney stones.

DOI：
10.1038/nrdp.2016.8
发表时间：
2016-02-25
期刊：
Nature reviews. Disease primers
影响因子：
0
作者：
Khan SR;Pearle MS;Robertson WG;Gambaro G;Canales BK;Doizi S;Traxer O;Tiselius HG
通讯作者：
Tiselius HG

Exposure of Madin-Darby canine kidney (MDCK) cells to oxalate and calcium oxalate crystals activates nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase.