权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of BK Channel in Chronic Kidney Disease

BK 通道在慢性肾脏病中的作用

基本信息

批准号：
10620115
负责人：
HUI CAI
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620115
关键词：
Adult Affect Automobile Driving Biopsy Specimen Blood Vessels Cell Aging Cell Cycle Arrest Cell Line Cell Separation Cells Chronic Kidney Failure Clinical Clinical Trials Data Development Diabetic Nephropathy Disease model End stage renal failure Etiology Excretory function Experimental Models Fatty acid glycerol esters Fibroblasts Fibrosis Focal and Segmental Glomerulosclerosis Folic Acid Human Kidney Kidney Diseases Knock-out Knockout Mice Literature Mediating Membrane Microdomains Modeling Molecular Mus Obese Mice Pathogenesis Pathway interactions Patients Phase Play Potassium Potassium Channel Profibrotic signal Protein Isoforms Public Health Rattus Reporting Role Severities Signal Pathway Testing Time Transforming Growth Factor beta Translating Tubular formation Ureteral obstruction Veterans Wild Type Mouse cytokine insight interstitial kidney biopsy kidney fibrosis large-conductance calcium-activated potassium channels mouse model novel prevent renal epithelium therapeutic target

项目摘要

Project Summary Chronic kidney disease (CKD) affects 26–30 million U.S. adults and remains a major public health problem (1; 2). Renal fibrosis is the inevitable consequence of almost every type of CKD regardless of underlying etiology, and leads to progressive renal failure and end-stage of renal disease (ESRD) (1). Thus, preventing renal fibrosis may in turn prevent progression of CKD and ESRD. While there is compelling literature suggesting many potential therapeutic targets for treating renal fibrosis, very few have advanced to the initial phase of clinical trials (3; 4), and none have shown efficacy in the treatment of renal fibrosis (4). Thus, it is crucial to continue to discover and test novel potential therapeutic targets for renal fibrosis. Unilateral ureteral obstruction (UUO) is a common and well-validated renal fibrosis experimental model. Transforming growth factor-beta (TGF-β) isoforms are multifunctional cytokines that play a central role in driving fibrosis in most, if not all, forms of CKD (5). Big potassium (BK) channels (also called Big-K, Maxi-K or Slo1 channels) are K+ channels and may be one novel target that plays a major role in renal fibrosis. BK channels consist of the α-subunit (BKα), which functions as a channel independently, β-subunits (β1-4), and the γ-subunit (6; 7). A recent study reported that BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodeling in high-fat fed obesity mice, suggesting that reduced BKα sensitivity and activity caused by β1 deficiency (8) leads to vascular fibrosis (9). We have compelling preliminary evidence that shows for the first time that BKα also plays a critical role in renal fibrosis. While BKα knockout (KO) mice were prone to developing more severe fibrosis after UUO (Figure 1), pre-treatment with the BK channel opener, BMS191011 (Sigma-Aldrich, SML0866), that can activate BK channels (10), protected mice from developing renal fibrosis in wild-type (WT) UUO mice (Figure 2) by suppressing TGF-β1 signaling pathway (Figures 3-4). These data suggest that the BK channel plays an important role in the development of renal fibrosis. Thus, elucidating the mechanisms underlying the role of BK channel in the pathogenesis of renal fibrosis is of utmost clinical importance. Our overall hypothesis is that BK channel deficiency is prone to developing renal fibrosis via activating the TGF-β signaling pathway in renal fibrotic mouse models. In this application we will propose three specific aims to test our overall hypothesis: Specific Aim 1: To validate the role of the BK channels in the development of renal fibrosis in different renal fibrosis mouse models. Specific Aim 2: To investigate the molecular mechanisms underlying the BK-mediated development of renal fibrosis. Specific Aim 3: To translate the experimental findings by examining whether BK expression levels are correlated with the severity of renal fibrosis in CKD patients. SA3.1. Determine whether BK expression levels are quantifiably correlated to the severity of renal fibrosis in kidney biopsy samples from CKD patients with diabetic nephropathy and focal segmental glomerulosclerosis (FSGS). Elucidation of the molecular mechanisms underlying the BK-mediated development of renal fibrosis will provide novel insights into whether BK channels can be utilized as a potential therapeutic target for treating CKD patients and preventing them from progressing to ESRD.

项目摘要慢性肾脏疾病（CKD）影响着2600万至3000万美国成年人，仍然是一个主要的公共卫生问题。（1; 2）。肾纤维化是几乎所有类型的CKD的不可避免的后果，无论其基础如何。病因，并导致进行性肾衰竭和终末期肾病（ESRD）（1）。从而防止肾纤维化可反过来阻止CKD和ESRD的进展。虽然有令人信服的文献提示了许多治疗肾纤维化的潜在治疗靶点，但很少有进展到最初的治疗靶点。临床试验阶段（3; 4），没有一个显示出在治疗肾纤维化方面的疗效（4）。照经上所这对于继续发现和测试肾纤维化的新的潜在治疗靶点至关重要。单侧输尿管梗阻（UUO）是一种常见的肾纤维化模型。转化生长因子-β（TGF-β）同种型是多功能细胞因子，其在肿瘤生长中起核心作用。在大多数（如果不是全部）CKD形式中驱动纤维化（5）。大钾（BK）通道（也称为Big-K、Maxi-K或 Slo 1通道）是K+通道，并且可能是在肾纤维化中起主要作用的一个新靶点。BK 通道由独立发挥通道功能的α亚基（BKα）、β亚基（β1-4）和 γ亚基（6; 7）。最近的一项研究报道，BK通道β1亚基缺乏可加重血管性痴呆，高脂喂养的肥胖小鼠的纤维化和重塑，表明BKα敏感性和活性降低由β1缺乏引起的血管纤维化（8）导致血管纤维化（9）。我们有令人信服的初步证据表明 BKα首次在肾纤维化中发挥关键作用。而BKα基因敲除（KO）小鼠在UUO后发展更严重的纤维化（图1），用BK通道开放剂预处理，可以激活BK通道的BMS 191011（Sigma-Aldrich，SML 0866）（10）保护小鼠免于发育在野生型（WT）UUO小鼠中，通过抑制TGF-β1信号传导途径（图3-4）抑制肾纤维化（图2）。这些数据表明，BK通道在肾纤维化的发展中起着重要作用。因此，阐明BK通道在肾纤维化发病机制中的作用机制是重要的。最重要的临床意义。我们的总体假设是，BK通道缺乏倾向于发展通过激活TGF-β信号通路在肾纤维化小鼠模型中治疗肾纤维化。在这我们将提出三个具体目标来测试我们的总体假设：具体目的1：验证BK通道在肾纤维化发展中的作用，不同的肾纤维化小鼠模型。具体目标2：研究BK介导的发展的分子机制肾纤维化具体目标3：通过检查BK表达水平是否与CKD患者肾纤维化的严重程度相关。 SA3.1.确定BK表达水平是否与肾纤维化的严重程度定量相关，来自患有糖尿病肾病和局灶节段性肾小球硬化症的CKD患者的肾活检样本（FSGS）。阐明BK介导的肾纤维化发展的分子机制将有助于为BK通道是否可以用作治疗的潜在治疗靶点提供了新的见解， CKD患者并防止他们进展为ESRD。