Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Department of Ultrasound, Chongqing Key Laboratory of Ultrasound, Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cell Commun Signal. 2024 Jan 30;22(1):78. doi: 10.1186/s12964-024-01481-5.
Renal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis.
Male C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms.
Succinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3β/β-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells.
The causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3β/β-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.
肾纤维化是慢性肾脏病（CKD）导致肾功能进行性丧失的主要原因，而交替激活的 M2 巨噬细胞在这一进展中起着至关重要的作用。琥珀酸水平在糖尿病和肥胖患者中持续升高，这两者都是导致 CKD 的关键因素。然而，目前尚不清楚琥珀酸水平升高是否能介导巨噬细胞 M2 极化并导致肾间质纤维化。
雄性 C57/BL6 小鼠给予添加 4%琥珀酸的水 12 周，以评估其对肾间质纤维化的影响。此外，还通过使用氯膦酸盐脂质体消耗巨噬细胞来体内验证巨噬细胞的重要性。此外，我们还采用 RAW 264.7 和 NRK-49F 细胞来研究潜在的分子机制。
琥珀酸导致肾间质巨噬细胞浸润、促纤维化 M2 表型激活、促纤维化因子上调和间质纤维化。氯膦酸盐脂质体处理显著消耗巨噬细胞，并防止琥珀酸诱导的促纤维化因子和纤维化增加。机制上，琥珀酸通过触发 SUCNR1-p-Akt/p-GSK3β/β-catenin 信号通路促进 CTGF 转录，该信号通路被 SUCNR1 siRNA 抑制。琥珀酸受体（SUCNR1）敲低或 SUCNR1 预处理抑制了琥珀酸对 RAW 264.7 和 NRK-49F 细胞的刺激作用。
琥珀酸对肾间质纤维化的因果作用是通过激活促纤维化 M2 巨噬细胞介导的。琥珀酸-SUCNR1 激活 p-Akt/p-GSK3β/β-catenin、CTGF 表达，并促进巨噬细胞和成纤维细胞之间的串扰。我们的研究结果表明，通过促进尿中琥珀酸的排泄和/或使用 SUCNR1 的选择性拮抗剂，可能是预防代谢性 CKD 进展的一种有前途的策略。
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