Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea.
J Am Soc Nephrol. 2023 May 1;34(5):809-828. doi: 10.1681/ASN.0000000000000075. Epub 2023 Jan 21.
Mesangial cells (MCs) in the kidney are essential to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying mechanism is poorly understood. We show that YAP/TAZ are increased in MCs of patients with DN and two animal models of DN. High glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse MCs recapitulates the hallmarks of DN. Activated YAP/TAZ bind and stabilize N-Myc, one of the Myc family. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and to MC impairments. Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.
Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases, including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood.
Immunolocalization of YAP/TAZ and pathological features of PDGFRβ + MCs were analyzed in the glomeruli of patients with DN, in Zucker diabetic fatty rats, and in Lats1/2i ΔPβ mice. RiboTag bulk-RNA sequencing and transcriptomic analysis of gene expression profiles of the isolated MCs from control and Lats1/2iΔPβ mice were performed. Immunoprecipitation analysis and protein stability of N-Myc were performed by the standard protocols.
YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and in Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis.
Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.
肾脏中的系膜细胞（MCs）对于维持肾小球完整性至关重要，其损伤会导致包括糖尿病肾病（DN）在内的主要肾小球疾病。尽管高血糖会引起 MCs 的异常改变，但其中的潜在机制尚不清楚。我们发现，DN 患者和两种 DN 动物模型的 MCs 中 YAP/TAZ 增加。高葡萄糖在培养的 MCs 中通过经典 Hippo 通路直接诱导 YAP/TAZ 的激活。在小鼠 MCs 中过度激活 YAP/TAZ 可重现 DN 的特征。激活的 YAP/TAZ 结合并稳定 N-Myc，即 Myc 家族的一种。N-Myc 的稳定导致其转录活性的异常增强，从而导致 MCs 损伤。我们的研究结果阐明了糖尿病中高血糖如何导致 DN，并支持了降低糖尿病中血糖水平可能延缓 DN 发病机制的观点。
肾脏中的系膜细胞（MCs）对于维持肾小球完整性至关重要，其损伤会导致包括糖尿病肾病（DN）在内的主要肾小球疾病。尽管高血糖会引起 MCs 的异常改变，但其中的潜在分子机制尚不清楚。
通过免疫组化分析 DN 患者、Zucker 糖尿病肥胖大鼠和 Lats1/2iΔPβ 小鼠肾小球中的 YAP/TAZ 和 PDGFRβ+MC 的病理特征。对来自对照和 Lats1/2iΔPβ 小鼠的分离 MC 进行核糖体标签批量 RNA 测序和基因表达谱的转录组分析。通过标准方案进行 N-Myc 的免疫沉淀分析和蛋白质稳定性分析。
Hippo 通路的最终效应物 YAP 和 TAZ 在 DN 患者和 Zucker 糖尿病肥胖大鼠的 MCs 中高度增加。此外，高葡萄糖在培养的 MCs 中通过经典 Hippo 通路直接诱导 YAP/TAZ 的激活。在小鼠模型 MCs 中过度激活 YAP/TAZ 可重现 DN 的特征，包括 MCs 的过度增殖和细胞外基质沉积、内皮细胞损伤、肾小球硬化、白蛋白尿和肾小球滤过率降低。在机制上，激活的 YAP/TAZ 结合并稳定 N-Myc 蛋白，即 Myc 家族的一种致癌基因。N-Myc 的稳定导致其转录活性的异常增强，最终导致 MCs 损伤和 DN 发病机制。
我们的研究结果阐明了糖尿病中高血糖如何导致 DN，并支持了降低糖尿病中血糖水平可能延缓 DN 发病机制的观点。
