Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Am J Physiol Renal Physiol. 2022 Aug 1;323(2):F227-F242. doi: 10.1152/ajprenal.00452.2021. Epub 2022 Jun 27.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder that is caused by mutations in or genes and is characterized by renal fluid-filled cyst formation and interstitial fibrosis. gene mutation results in the upregulation of SET (suppressor of variegation, enhancer of zeste, trithorax) and MYND (myeloid-nervy-DEAF1) domain-containing lysine methyltransferase 2 (SMYD2) in kidneys from mutant mice and patients with ADPKD. However, the role and mechanism of Smyd2 in the regulation of renal fibrosis in ADPKD remains elusive. In the present study, we showed that ) expression of Smyd2 can be regulated by transforming growth factor (TGF)-β-Smad3 in normal rat kidney 49F (NRK-49F) cells and mouse fibroblast NIH3T3 cells; ) knockdown of Smyd2 and inhibition of Smyd2 with its specific inhibitor, AZ505, decreases TGF-β-induced expression of α-smooth muscle actin, fibronectin, collagen type 1 and 3, and plasminogen activator inhibitor-1 in NRK-49F cells; ) Smyd2 regulates the transcription of fibrotic marker genes through binding on the promoters of those genes or through methylating histone H3 to indirectly regulate the expression of those genes; and ) knockout and inhibition of Smyd2 significantly decreases renal fibrosis in knockout mice, supporting that targeting Smyd2 can not only delay cyst growth but also attenuate renal fibrosis in ADPKD. This study identified a cross talk between TGF-β signaling and Smyd2 in the regulation of fibrotic gene transcription and activation of fibroblasts in cystic kidneys, suggesting that targeting Smyd2 with AZ505 is a potential therapeutic strategy for ADPKD treatment. Here, we identified a cross talk between SET and MYND domain-containing lysine methyltransferase 2 (Smyd2) and transforming growth factor (TGF)-β-Smad3 signaling and a synergistic feedback loop between them, in which TGF-β stimulates expression of Smyd2 in a Smad3-dependent manner, and upregulation of Smyd2 regulates the transcription of TGF-β and other fibrotic marker genes through direct binding on their promoters or methylating histone H3 indirectly to regulate the transcription of those genes in fibroblasts. Thus, the Smyd2-TGF-β-Smad3-Smyd2 signaling axis plays an important role in promoting renal fibrosis, and targeting Smyd2 with its specific inhibitor should not only delay cyst growth but also ameliorate renal fibrosis in ADPKD.
常染色体显性多囊肾病（ADPKD）是一种遗传性遗传疾病，由 或 基因突变引起，其特征是肾脏充满液体的囊肿形成和间质纤维化。 基因突变导致突变小鼠肾脏和 ADPKD 患者的 SET（变异抑制、增强子 Zeste、trithorax）和 MYND（骨髓-神经-DEAF1）结构域包含赖氨酸甲基转移酶 2（SMYD2）上调。然而，Smyd2 在调节 ADPKD 肾纤维化中的作用和机制仍不清楚。在本研究中，我们表明：1）Smyd2 的表达可以被转化生长因子（TGF）-β-Smad3 在正常大鼠肾 49F（NRK-49F）细胞和小鼠成纤维细胞 NIH3T3 细胞中调节；2）Smyd2 的敲低和其特异性抑制剂 AZ505 的抑制降低了 TGF-β 诱导的 NRK-49F 细胞中α-平滑肌肌动蛋白、纤维连接蛋白、胶原 1 和 3 和纤溶酶原激活物抑制剂-1 的表达；3）Smyd2 通过结合在这些基因的启动子上或通过甲基化组蛋白 H3 来调节纤维化标记基因的转录，从而间接调节这些基因的表达；4）Smyd2 敲除和抑制显著减少了 敲除小鼠的肾纤维化，支持靶向 Smyd2 不仅可以延迟囊肿生长，还可以减轻 ADPKD 中的肾纤维化。本研究鉴定了 TGF-β 信号与 Smyd2 之间在囊性肾脏中调节纤维化基因转录和成纤维细胞激活的交叉对话，提示用 AZ505 靶向 Smyd2 是治疗 ADPKD 的潜在治疗策略。在这里，我们鉴定了 SET 和 MYND 结构域包含赖氨酸甲基转移酶 2（Smyd2）和转化生长因子（TGF）-β-Smad3 信号之间的交叉对话，以及它们之间的协同反馈回路，其中 TGF-β 以 Smad3 依赖的方式刺激 Smyd2 的表达，而上调的 Smyd2 通过直接结合其启动子或甲基化组蛋白 H3 间接调节这些基因的转录，从而调节成纤维细胞中这些基因的转录。因此，Smyd2-TGF-β-Smad3-Smyd2 信号轴在促进肾纤维化中起重要作用，用其特异性抑制剂靶向 Smyd2 不仅可以延迟囊肿生长，还可以改善 ADPKD 中的肾纤维化。
