Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
University of Science and Technology, Daejeon, Korea.
J Cell Mol Med. 2020 Aug;24(15):8814-8825. doi: 10.1111/jcmm.15519. Epub 2020 Jun 22.
The growth arrest and DNA damage-inducible beta (Gadd45β) protein have been associated with various cellular functions, but its role in progressive renal disease is currently unknown. Here, we examined the effect of Gadd45β deletion on cell proliferation and apoptosis, inflammation, and renal fibrosis in an early chronic kidney disease (CKD) mouse model following unilateral ureteral obstruction (UUO). Wild-type (WT) and Gadd45β-knockout (KO) mice underwent either a sham operation or UUO and the kidneys were sampled eight days later. A histological assay revealed that ablation of Gadd45β ameliorated UUO-induced renal injury. Cell proliferation was higher in Gadd45β KO mouse kidneys, but apoptosis was similar in both genotypes after UUO. Expression of pro-inflammatory cytokines after UUO was down-regulated in the kidneys from Gadd45β KO mice, whereas UUO-mediated immune cell infiltration remained unchanged. The expression of pro-inflammatory cytokines in response to LPS stimulation decreased in bone marrow-derived macrophages from Gadd45β KO mice compared with that in WT mice. Importantly, UUO-induced renal fibrosis was ameliorated in Gadd45β KO mice unlike in WT mice. Gadd45β was involved in TGF-β signalling pathway regulation in kidney fibroblasts. Our findings demonstrate that Gadd45β plays a crucial role in renal injury and may be a therapeutic target for the treatment of CKD.
生长停滞和 DNA 损伤诱导因子β（Gadd45β）蛋白与各种细胞功能有关，但它在进行性肾脏疾病中的作用目前尚不清楚。在这里，我们研究了 Gadd45β 缺失对单侧输尿管梗阻（UUO）后早期慢性肾脏病（CKD）小鼠模型中细胞增殖和细胞凋亡、炎症和肾纤维化的影响。野生型（WT）和 Gadd45β 敲除（KO）小鼠接受假手术或 UUO 手术，8 天后采集肾脏样本。组织学检测结果表明，Gadd45β 缺失可改善 UUO 诱导的肾脏损伤。Gadd45β KO 小鼠肾脏中的细胞增殖更高，但 UUO 后两种基因型的细胞凋亡相似。UUO 后，Gadd45β KO 小鼠肾脏中促炎细胞因子的表达下调，而 UUO 介导的免疫细胞浸润保持不变。与 WT 小鼠相比，Gadd45β KO 小鼠骨髓来源的巨噬细胞对 LPS 刺激的促炎细胞因子表达降低。重要的是，与 WT 小鼠相比，UUO 诱导的肾纤维化在 Gadd45β KO 小鼠中得到改善。Gadd45β 参与了肾成纤维细胞中 TGF-β 信号通路的调节。我们的研究结果表明，Gadd45β 在肾脏损伤中起关键作用，可能是治疗 CKD 的治疗靶点。
