Role of M1 Cytokines in the Progression of Chronic Kidney Disease

M1 细胞因子在慢性肾脏病进展中的作用

• 批准号: 10347185
• 负责人: Steven D Crowley
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347185
• 关键词: Architecture; Aristolochic Acids; Attenuated; Autoimmunity; Cardiovascular Diseases; Cardiovascular system; Cell Cycle Arrest; Cells; Chronic; Chronic Kidney Failure; Cisplatin; Disease; Disease Progression; Disease model; End stage renal failure; GKLF protein; Generations; Immunotherapy; Inflammation; Inflammation Mediators; Inflammatory; Injury; Injury to Kidney; Interleukin-1; Interruption; Ischemia; Kidney; Kidney Diseases; Kidney Neoplasms; Kruppel-like transcription factors; Ligands; Modeling; Molecular Analysis; Mus; Myeloid Cells; Nephritis; Nephrons; Obstruction; Organ failure; Pathway interactions; Pattern; Porcupines; Predisposition; Prevention therapy; Protein Isoforms; Proteins; Reperfusion Therapy; Reporting; Role; Serum; Severities; Severity of illness; Signal Transduction; Site; Sterility; TNF gene; Testing; Toxin; Transferase; Tubular formation; Tumor Necrosis Factor Suppression; Tumor-infiltrating immune cells; Ubiquitin; Veterans; WNT Signaling Pathway; cardiovascular risk factor; cell injury; cytokine; cytotoxicity; injured; kidney fibrosis; macrophage; military veteran; mouse model; nephrotoxicity; novel therapeutics; preservation; prevent; rational design; renal damage; repaired

Macrophages can have profound effects on the progression of chronic kidney disease (CKD) via the secretion of pro-inflammatory “M1” cytokines including tumor necrosis factor- (TNF) and Interleukin-1 (IL-1). In the previous cycle, we established that the transcription factor Krüppel like factor 4 in macrophages limits kidney damage and fibrosis by suppressing macrophage TNF expression. However, TNF and IL-1 are also produced by renal tubular cells (RTCs), and our preliminary studies have identified 2 factors in RTCs, A20 and Porcupine (PORCN), that together constrain local TNF and IL-1 generation and ameliorate CKD. A20 is a ubiquitin editing protein that downregulates NF-b signaling in myeloid cells and thereby protects against autoimmunity. In our preliminary studies using murine models of inflammation- and toxin-induced renal injury, deletion of A20 selectively from RTCs (A20 KKO) permits enhanced local TNF and IL-1 expression and exacerbations in RTC damage. We therefore hypothesize that A20 in the nephron protects against tubular damage and subsequent CKD by constraining local generation of TNF and IL-1. To test this, we will subject A20 KKO and littermate controls to models of chronic renal tubular injury. We recently reported that TNF in RTCs induces several Wnt ligand isoforms and that the secretion of Wnt ligands permitted by the O-acyl transferase Porcupine exaggerates obstruction-induced renal fibrosis. By contrast, in other models featuring proximal tubular injury Wnt signaling can protect against CKD progression, and in our preliminary studies, inducible nephron-specific deletion of PORCN upregulates renal TNF expression and exacerbates nephrotoxic serum nephritis (NTS). As restoring - catenin signals can protect the proximal tubule, a key site of TNF-induced injury, we posit that PORCN in proximal tubular cells suppresses TNF expression and thereby limits the severity of CKD. To test this hypothesis, we will subject mice lacking PORCN in the proximal tubule (PORCN PTKO) to our tubular injury models. Our preliminary studies indicate that deleting TNF from the proximal tubule (TNF PTKO) mitigates toxin-induced tubular damage and prevents cell cycle arrest. Thus, to directly interrogate whether PORCN-dependent secretion in the proximal tubule limits CKD severity by suppressing TNF-induced cytotoxicity, we will compare the susceptibility to RTC damage of PORCN PTKO mice and mice harboring double PORCN and TNF deletion restricted to the proximal tubule (Dual PTKO). We predict that interrupting TNF’s actions in the proximal tubule will abrogate the augmented susceptibility to CKD accruing from PORCN deficiency in the proximal tubule. With our integrated approach, we will elucidate nephron-specific pathways upstream and downstream of TNF that can be targeted for the amelioration of CKD.

巨噬细胞可通过分泌巨噬细胞对慢性肾脏疾病(CKD)的进展产生深远影响。 促炎症的“M1”细胞因子，包括肿瘤坏死因子-和白介素1-(IL-1)。在 在之前的周期中，我们发现巨噬细胞中的转录因子Krüppel样因子4限制了肾脏 通过抑制巨噬细胞肿瘤坏死因子的表达造成损伤和纤维化。然而，肿瘤坏死因子和白介素1也会产生 通过肾小管细胞(RTCs)，我们的初步研究确定了RTCs中的两个因子，A20和豪猪 (PORCN)，共同抑制局部肿瘤坏死因子和IL-1的产生，改善慢性肾脏病。A20是一种泛在编辑 在髓系细胞中下调核因子-b信号从而保护自身免疫的蛋白质。在我们的 利用炎症和毒素诱导的小鼠肾损伤模型的初步研究，缺失A20 选择性地从RTCs(A20kko)可促进局部肿瘤坏死因子和IL-1的表达，并使RTC恶化 损坏。因此，我们假设肾单位中的A20可以保护肾小管不受损伤 通过抑制局部产生肿瘤坏死因子和白介素1来治疗慢性肾功能不全。为了测试这一点，我们将测试20千克和窝产仔 慢性肾小管损伤模型的对照研究。我们最近报道，RTCs中的肿瘤坏死因子可诱导多个WNT 配体异构体和豪猪O-酰基转移酶允许的Wnt配体的分泌被夸大 梗阻性肾纤维化。相比之下，在其他以近端肾小管损伤为特征的模型中，Wnt信号转导 可以防止CKD的进展，在我们的初步研究中，可诱导的肾单位特异性缺失 PORCN上调肾脏肿瘤坏死因子的表达，加重肾毒性血清肾炎(NTS)。AS正在恢复- 连环蛋白信号对肿瘤坏死因子诱导损伤的关键部位--近端小管具有保护作用，我们推测PORCN在 近端肾小管上皮细胞抑制肿瘤坏死因子的表达，从而限制慢性肾脏病的严重程度。为了检验这一假设， 我们将使近端小管中缺乏PORCN(PORCN PTKO)的小鼠接受我们的肾小管损伤模型。我们的 初步研究表明，从近端小管中删除肿瘤坏死因子(TNF PTKO)可减轻毒素诱导的 肾小管损伤，防止细胞周期停滞。因此，要直接询问PORCN依赖的分泌物 在近端小管通过抑制肿瘤坏死因子诱导的细胞毒性来限制CKD的严重程度，我们将比较 PORCN PTKO小鼠和PORCN和TNF双缺失小鼠对RTC损伤的易感性 局限于近端小管(双PTKO)。我们预测，阻断肿瘤坏死因子在近端小管的作用 将消除由于近端小管PORCN缺乏而增加的CKD易感性。使用 在我们的综合方法中，我们将阐明肿瘤坏死因子的上游和下游的肾单位特异性通路 可作为CKD改善的靶点。