|
|
|
| Aggravation of macrophage-mediated inflammatory damage by knockdown of Nrf2 in a unilateral ureteral obstruction renal fibrosis model |
| WU Cunzao1, LU Hong2, ZHU Hengyue2, WENG Min1, SHI Chenghao1, LIN Zhouhao1, BAI Yongheng3 |
| 1.Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; 2.Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; 3.Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China |
|
| Cite this article: |
|
WU Cunzao,LU Hong,ZHU Hengyue, et al. Aggravation of macrophage-mediated inflammatory damage by knockdown of Nrf2 in a unilateral ureteral obstruction renal fibrosis model[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2021, 51(6): 437-443.
|
|
|
|
Abstract Objective: To study the mechanism of Nrf2 gene knockout and its effect on inflammatory injury in unilateral ureteral obstruction (UUO) renal fibrosis model. Methods: The experimental mice were randomly divided into four groups, namely Nrf2 wild-type UUO group (Nrf2Wild-type UUO), Nrf2 knockout UUO group (Nrf2KO UUO), Nrf2 wild-type sham operation group ( Nrf2Wild-type Sham) and Nrf2 gene knockout sham operation group (Nrf2KO Sham), with 6 animals in each group. PAS and Masson staining was used to detect tissue damage and total collagen accumulation; immunohistochemical staining was used to detect the expression of macrophage marker CD68 and IRF5; ELISA was used to detect the level of iNOS; qRT-PCR was used to detect the mRNA expression of pro-inflammatory genes IL-1β, IL-6 and TNF-α. The protein expression of IRF5 was determined by Western blot. Results: PAS staining showed that Nrf2 gene knockout did not cause renal tissue damage, but after the UUO model was constructed, the renal tissue damage significantly increased. The results of Masson and immunochemical staining showed that Nrf2 gene knockout aggravated the degree of interstitial fibrosis in the UUO model, and promoted the infiltration of CD68-positive macrophages, accompanied with the enhancement of iNOS level. Further study found that compared with Nrf2Wild-type UUO group, the mRNA expression levels of IL-1β, IL-6, and TNF-α in the kidney tissues in the Nrf2KO UUO group were significantly increased (P<0.05). At the same time, Western blot and immunochemical staining results showed that Nrf2 gene knockout increased the expression of IRF5 protein (P<0.05). Conclusion: Nrf2 gene knockout aggravates the inflammatory damage in the UUO renal fibrosis model, and its mechanism may be related to the promotion of IRF5-mediated infiltration of inflammatory macrophages, thereby increasing the synthesis and release of inflammatory factors.
|
|
Received: 06 March 2021
|
| |
|
|
|
参考文献：
[1] ULLAH M M, BASILE D P. Role of renal hypoxia in the progression from acute kidney injury to chronic kidney disease[J]. Semin Nephrol, 2019, 39(6): 567-580.
[2] TANG P M, NIKOLIC-PATERSON D J, LAN H Y. Macrophages: versatile players in renal inflammation and fibrosis[J]. Nat Rev Nephrol, 2019, 15(3): 144-158.
[3] WU S, LU H, BAI Y. Nrf2 in cancers: A double edged sword [J]. Cancer Med, 2019, 8(5): 2252-2267.
[4] SAHA S, BUTTARI B, PANIERI E, et al. An overview of Nrf2 signaling pathway and its role in inflammation[J]. Molecules, 2020, 25(22): 5474.
[5] GUO Y, XIAO Y, ZHU H, et al. Inhibition of proliferation-linked signaling cascades with atractylenolide I reduces myofibroblastic phenotype and renal fibrosis[J]. Biochem Pharmacol, 2021, 183: 114344.
[6] SHELTON L M, PARK B K, COPPLE I M. Role of Nrf2 in protection against acute kidney injury[J]. Kidney Int, 2013, 84(6): 1090-1095.
[7] KONG W, FU J, LIU N, et al. Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction[J]. Nephrol Dial Transplant, 2018, 33(5): 771-783.
[8] POTTETI H R, NOONE P M, TAMATAM C R, et al. Nrf2 mediates hypoxia-inducible HIF1α activation in kidney tubular epithelial cells[J]. Am J Physiol Renal Physiol, 2021, 320(3): F464-F474.
[9] GUERRERO-HUE M, RAYEGO-MATEOS S, VÁZQUEZ-CARBALLO C, et al. Protective role of Nrf2 in renal disease[J]. Antioxidants (Basel), 2020, 10(1): 39.
[10] 吴莲凤, 陆红, 洪炜龙, 等. M1/M2巨噬细胞极化参与肾组织炎症损伤和修复进程的作用机制[J]. 中国病理生理杂志, 2017, 33(12): 2245-2251.
[11] CAO Q, WANG Y, HARRIS D C. Macrophage heterogeneity, phenotypes, and roles in renal fibrosis[J]. Kidney Int Suppl (2011), 2014, 4(1): 16-19.
[12] KRAUSGRUBER T, BLAZEK K, SMALLIE T, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses[J]. Nat Immunol, 2011, 12(3): 231-238.
[13] CORBIN A L, GOMEZ-VAZQUEZ M, BERTHOLD D L, et al. IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation[J]. Sci Immunol, 2020, 5(47): eaax6085.
[14] FAN Z, ZHAO S, ZHU Y, et al. Interferon regulatory factor 5 Mediates lipopolysaccharide-induced neuroinflammation [J]. Front Immunol, 2020, 11: 600479. |
|
|
|
