Role of BK Channel in Chronic Kidney Disease

BK 通道在慢性肾脏病中的作用

• 批准号: 10367944
• 负责人: HUI CAI
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 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/10367944
• 关键词: Adult; Affect; Automobile Driving; Biopsy Specimen; Blood Vessels; Cell Aging; Cell Cycle Arrest; Cell Line; 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 Segmental Glomerulosclerosis; Folic Acid; Human; Kidney; Kidney Failure; 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; TGF Beta Signaling 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

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.

项目概要 慢性肾病 (CKD) 影响着 26-3000 万美国成年人，并且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 CKD 的不可避免的结果，无论其基础是什么 病因学，并导致进行性肾衰竭和终末期肾病 (ESRD) (1)。因此，防止 肾纤维化可能进而预防 CKD 和 ESRD 的进展。虽然有引人注目的文献 表明治疗肾纤维化有许多潜在的治疗靶点，但很少有进展到最初的治疗靶点 临床试验阶段 (3; 4)，但尚未显示出治疗肾纤维化的功效 (4)。因此，它是 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）是一种常见且经过充分验证的肾纤维化实验模型。 转化生长因子-β (TGF-β) 同工型是多功能细胞因子，在 在大多数（如果不是全部）形式的 CKD 中导致纤维化 (5)。大钾 (BK) 通道（也称为 Big-K、Maxi-K 或 Slo1 通道）是 K+ 通道，可能是在肾纤维化中起主要作用的一个新靶点。巴克 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)。最近的一项研究报告称，BK 通道 β1 亚基缺乏会加剧血管 高脂肪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 (8) 会导致血管纤维化 (9)。我们有令人信服的初步证据表明 首次发现 BKα 在肾纤维化中也发挥着关键作用。而 BKα 敲除 (KO) 小鼠则容易 UUO（图 1）、BK 通道开放剂预处理后出现更严重的纤维化， BMS191011（Sigma-Aldrich，SML0866），可以激活 BK 通道 (10)，保护小鼠免于发育 通过抑制 TGF-β1 信号通路（图 3-4）来抑制野生型 (WT) UUO 小鼠的肾纤维化（图 2）。 这些数据表明BK通道在肾纤维化的发展中发挥重要作用。 因此，阐明 BK 通道在肾纤维化发病机制中的作用机制具有重要意义。 极其重要的临床意义。我们的总体假设是 BK 通道缺陷很容易发生 通过激活肾纤维化小鼠模型中的 TGF-β 信号通路来抑制肾纤维化。在这个 在应用程序中，我们将提出三个具体目标来检验我们的总体假设： 具体目标 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 介导的发育的分子机制 肾纤维化。 具体目标 3：通过检查 BK 表达水平是否正常来转化实验结果 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存在定量相关性 患有糖尿病肾病和局灶节段性肾小球硬化的 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 提供关于 BK 通道是否可以用作治疗的潜在治疗靶点的新见解 CKD 患者并防止他们进展为 ESRD。