Abstract：
OBJECTIVE: Renal fibrosis is a common feature in various chronic kidney diseases (CKD). Tubular cell damage is a main characterization which results from dysregulated fatty acid oxidation (FAO) and lipid accumulation. Cannabinoid Receptor 2 (CB2) contributes to renal fibrosis, however, its role in FAO dysregulation in tubular cells is not clarified. In this study, we found CB2 plays a detrimental role in lipid metabolism in tubular cells.
METHODS: CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, β-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of β-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed.
RESULTS: CB2 activates β-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to β-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2.
CONCLUSIONS: This study highlights CB2 disrupts FAO in tubular cells through β-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis.
METHODS: CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, β-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of β-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed.
RESULTS: CB2 activates β-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to β-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2.
CONCLUSIONS: This study highlights CB2 disrupts FAO in tubular cells through β-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis.
摘要：
目的：肾纤维化是各种慢性肾脏病（CKD）的共同特征。肾小管细胞损伤是由异常调节的脂肪酸氧化(FAO)和脂质积累引起的主要特征。大麻素受体2（CB2）有助于肾纤维化，然而,其在FAO在肾小管细胞失调中的作用尚不清楚。在这项研究中,我们发现CB2在肾小管细胞的脂质代谢中起着有害作用.
方法：采用CB2基因敲除小鼠建立叶酸肾病(FAN)模型。CB2引起的粮农组织功能障碍，脂质沉积，并在体内和体外评估纤维发生。探索分子机制，β-连环蛋白抑制剂和过氧化物酶体增殖物激活受体α（PPARα）激活剂也用于CB2过表达的细胞。分析了β-catenin在CB2抑制的PPARα和过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）激活中的中介作用。
结果：CB2激活β-连环蛋白信号，导致PPARα/PGC-1α轴的抑制。这降低了FAO的功能并导致肾小管细胞中的脂滴形成。CB2基因消融有效缓解FAO功能障碍，FAN小鼠的脂质沉积和尿毒症毒素积累，从而延缓肾脏纤维化。此外,抑制β-catenin或PPARα激活可以极大地抑制CB2诱导的脂质积累和纤维形成。
结论：本研究强调了CB2通过β-catenin激活和随后对PPARα/PGC-1α活性的抑制来破坏管状细胞中的FAO。对CB2的靶向抑制提供了对抗肾纤维化的前瞻性治疗策略。
方法：采用CB2基因敲除小鼠建立叶酸肾病(FAN)模型。CB2引起的粮农组织功能障碍，脂质沉积，并在体内和体外评估纤维发生。探索分子机制，β-连环蛋白抑制剂和过氧化物酶体增殖物激活受体α（PPARα）激活剂也用于CB2过表达的细胞。分析了β-catenin在CB2抑制的PPARα和过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）激活中的中介作用。
结果：CB2激活β-连环蛋白信号，导致PPARα/PGC-1α轴的抑制。这降低了FAO的功能并导致肾小管细胞中的脂滴形成。CB2基因消融有效缓解FAO功能障碍，FAN小鼠的脂质沉积和尿毒症毒素积累，从而延缓肾脏纤维化。此外,抑制β-catenin或PPARα激活可以极大地抑制CB2诱导的脂质积累和纤维形成。
结论：本研究强调了CB2通过β-catenin激活和随后对PPARα/PGC-1α活性的抑制来破坏管状细胞中的FAO。对CB2的靶向抑制提供了对抗肾纤维化的前瞻性治疗策略。
