Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
Biochim Biophys Acta Mol Basis Dis. 2022 Oct 1;1868(10):166474. doi: 10.1016/j.bbadis.2022.166474. Epub 2022 Jun 27.
A high-fat diet (HFD) is a major risk factor for chronic kidney disease. Although HFD promotes renal injury, characterized by increased inflammation and oxidative stress leading to fibrosis, the underlying mechanism remains elusive. Here, we investigated the role and mechanism of protease-activating receptor 2 (PAR2) activation during HFD-induced renal injury in C57/BL6 mice. HFD for 16 weeks resulted in kidney injury, manifested by increased blood levels of blood urea nitrogen, increased levels of oxidative stress with inflammation, and structural changes in the kidney tubules. HFD-fed kidneys showed elevated PAR2 expression level in the tubular epithelial region. To elucidate the role of PAR2, PAR2 knockout mice and their littermates were administered HFD. PAR2 deficient kidneys showed reduced extent of renal injury. PAR2 deficient kidneys showed significantly decreased levels of inflammatory gene expression and macrophage infiltration, followed by reduced accumulation of extracellular matrix proteins. Using NRK52E kidney epithelial cells, we further elucidated the mechanism and role of PAR2 activation during renal injury. Palmitate treatment increased PAR2 expression level in NRK52E cells and scavenging of oxidative stress blocked PAR2 expression. Under palmitate-treated conditions, PAR2 agonist-induced NF-κB activation level was higher with increased chemokine expression level in the cells. These changes were attenuated by the depletion of oxidative stress. Taken together, our results suggest that HFD-induced PAR2 activation is associated with increased levels of renal oxidative stress, inflammatory response, and fibrosis.
高脂肪饮食（HFD）是慢性肾脏病的主要危险因素。虽然 HFD 会促进肾脏损伤，表现为炎症和氧化应激增加导致纤维化，但潜在机制仍不清楚。在这里，我们研究了蛋白酶激活受体 2（PAR2）在 C57/BL6 小鼠 HFD 诱导的肾脏损伤中的作用和机制。HFD 喂养 16 周导致肾脏损伤，表现为血尿素氮水平升高、氧化应激水平升高伴炎症以及肾小管结构改变。HFD 喂养的肾脏中肾小管上皮区域的 PAR2 表达水平升高。为了阐明 PAR2 的作用，PAR2 敲除小鼠及其同窝仔鼠给予 HFD。PAR2 缺陷型肾脏的肾损伤程度降低。PAR2 缺陷型肾脏的炎症基因表达和巨噬细胞浸润水平显著降低，随后细胞外基质蛋白的积累减少。使用 NRK52E 肾上皮细胞，我们进一步阐明了 PAR2 激活在肾脏损伤中的机制和作用。棕榈酸处理增加了 NRK52E 细胞中 PAR2 的表达水平，清除氧化应激可阻断 PAR2 的表达。在棕榈酸处理条件下，PAR2 激动剂诱导的 NF-κB 激活水平升高，细胞中的趋化因子表达水平升高。这些变化可被氧化应激耗竭所减弱。总之，我们的结果表明，HFD 诱导的 PAR2 激活与肾脏氧化应激、炎症反应和纤维化水平的增加有关。
