Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Cells. 2024 Mar 11;13(6):489. doi: 10.3390/cells13060489.
The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in mutant kidneys, and (3) decrease renal fibrosis in mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.
常染色体显性多囊肾病（ADPKD）是一种遗传性肾病，其进展与肾间质炎症和纤维化有关。CD74 不仅是巨噬细胞移动抑制因子（MIF）的受体，还具有 MIF 非依赖性功能。在这项研究中，我们报告了 CD74 在 ADPKD 中的未知作用和功能。我们发现，CD74 基因敲除可延缓突变肾脏中的囊肿生长。CD74 基因敲除和敲低（1）可使 PKD 相关信号通路正常化，包括 ERK、mTOR 和 Rb，从而减少突变肾脏上皮细胞的增殖，（2）减少 NF-κB 的激活和 MCP-1 和 TNF-α（TNF-α）的表达，从而减少突变肾脏中巨噬细胞的募集，以及（3）减少突变肾脏中的肾纤维化。我们首次表明，CD74 作为转录因子通过结合其启动子来调节纤维化标志物的表达，包括胶原 I（Col I）、纤连蛋白和α-平滑肌肌动蛋白（α-SMA）。有趣的是，CD74 还通过与其受体 CD74 结合来调节细胞内信号通路的活性，从而调节 MIF 的转录，在 ADPKD 肾脏中形成正反馈环，CD74 在囊肿进展过程中增加 MIF 的表达。我们进一步表明，MIF 基因敲除和用其抑制剂 ISO-1 靶向 MIF 不仅可以延缓囊肿生长，还可以通过阻断肾成纤维细胞的激活和 CD74 介导的 TGF-β-Smad3 信号转导来改善肾纤维化，这支持了 CD74 是囊肿生长和间质纤维化的关键和新型上游调节剂的观点。因此，靶向 MIF-CD74 轴是 ADPKD 治疗的一种新的治疗策略。
