Renal Division, Department of Internal medicine, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Cell Death Dis. 2021 Oct 13;12(10):943. doi: 10.1038/s41419-021-04214-5.
Transforming growth factor beta (TGFβ) signalling regulates extracellular matrix accumulation known to be essential for the pathogenesis of renal fibrosis; latent transforming growth factor beta binding protein 4 (LTBP4) is an important regulator of TGFβ activity. To date, the regulation of LTBP4 in renal fibrosis remains unknown. Herein, we report that LTBP4 is upregulated in patients with chronic kidney disease and fibrotic mice kidneys created by unilateral ureteral obstruction (UUO). Mice lacking the short LTBP4 isoform (Ltbp4S) exhibited aggravated tubular interstitial fibrosis (TIF) after UUO, indicating that LTBP4 potentially protects against TIF. Transcriptomic analysis of human proximal tubule cells overexpressing LTBP4 revealed that LTBP4 influences angiogenic pathways; moreover, these cells preserved better mitochondrial respiratory functions and expressed higher vascular endothelial growth factor A (VEGFA) compared to wild-type cells under hypoxia. Results of the tube formation assay revealed that additional LTBP4 in human umbilical vein endothelial cell supernatant stimulates angiogenesis with upregulated vascular endothelial growth factor receptors (VEGFRs). In vivo, aberrant angiogenesis, abnormal mitochondrial morphology and enhanced oxidative stress were observed in Ltbp4S mice after UUO. These results reveal novel molecular functions of LTBP4 stimulating angiogenesis and potentially impacting mitochondrial structure and function. Collectively, our findings indicate that LTBP4 protects against disease progression and may be of therapeutic use in renal fibrosis.
转化生长因子β（TGFβ）信号通路调节细胞外基质的积累，而细胞外基质的积累对于肾纤维化的发病机制至关重要；潜伏转化生长因子β结合蛋白 4（LTBP4）是 TGFβ活性的重要调节剂。迄今为止，LTBP4 在肾纤维化中的调控作用尚不清楚。本研究报道 LTBP4 在慢性肾脏病患者和单侧输尿管梗阻（UUO）所致纤维化小鼠肾脏中表达上调。缺乏短型 LTBP4 异构体（Ltbp4S）的小鼠在 UUO 后肾小管间质纤维化（TIF）加重，表明 LTBP4 可能对 TIF 有保护作用。对过表达 LTBP4 的人近端肾小管细胞进行转录组分析表明，LTBP4 影响血管生成途径；此外，与野生型细胞相比，这些细胞在缺氧条件下保持更好的线粒体呼吸功能，并表达更高水平的血管内皮生长因子 A（VEGFA）。管形成试验的结果表明，人脐静脉内皮细胞上清液中额外的 LTBP4 可刺激血管生成，上调血管内皮生长因子受体（VEGFRs）。在体内，UUO 后 Ltbp4S 小鼠出现异常血管生成、线粒体形态异常和氧化应激增强。这些结果揭示了 LTBP4 刺激血管生成的新分子功能，并可能影响线粒体的结构和功能。综上所述，我们的研究结果表明 LTBP4 可防止疾病进展，在肾纤维化中可能具有治疗作用。
