Kan Shuyan, Hou Qing, Shi Jinsong, Zhang Mingchao, Xu Feng, Liu Zhihong, Jiang Song
National Clinical Research Center for Kidney Disease, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Cell Death Discov. 2024 Jun 15;10(1):289. doi: 10.1038/s41420-024-02066-4.
Peroxisomal L-bifunctional enzyme (EHHADH) plays a role in the classic peroxisomal fatty acid β-oxidation pathway; however, the relationship between EHHADH expression and diabetic kidney disease has not been well understood. Here, we found that endogenous EHHADH levels were strongly correlated with the progression and severity of diabetic nephropathy in T2D patients. EHHADH knockout mice exhibited worsened renal tubular injury in diabetic mice. Furthermore, EHHADH is a modulator of pexophagy. In renal tubular epithelial cells (RTECs) in vitro, the knockdown of EHHADH induced a dramatic loss of peroxisomes. The loss of peroxisomes in EHHADH-deficient RTECs was restored by either an autophagic inhibitor 3-methyladenine or bafilomycin A1 both in vitro and in vivo. NBR1 was required for pexophagy in EHHADH-knockdown cells, where the level of reactive oxygen species (ROS) was increased, while inhibition of ROS blocked pexophagy. In summary, our findings revealed EHHADH deficiency accelerated renal injury in DKD as a modulator of pexophagy.
过氧化物酶体L-双功能酶（EHHADH）在经典的过氧化物酶体脂肪酸β-氧化途径中发挥作用；然而，EHHADH表达与糖尿病肾病之间的关系尚未得到充分了解。在此，我们发现内源性EHHADH水平与2型糖尿病患者糖尿病肾病的进展和严重程度密切相关。EHHADH基因敲除小鼠在糖尿病小鼠中表现出肾小管损伤加重。此外，EHHADH是pexophagy的调节因子。在体外肾小管上皮细胞（RTECs）中，EHHADH的敲低导致过氧化物酶体显著丢失。EHHADH缺陷型RTECs中过氧化物酶体的丢失在体外和体内均可通过自噬抑制剂3-甲基腺嘌呤或巴弗洛霉素A1恢复。NBR1是EHHADH敲低细胞中pexophagy所必需的，其中活性氧（ROS）水平升高，而抑制ROS可阻断pexophagy。总之，我们的研究结果表明，EHHADH缺陷作为pexophagy的调节因子加速了糖尿病肾病中的肾损伤。
