Interferon regulatory factor 4 deletion protects against kidney inflammation and fibrosis in deoxycorticosterone acetate/salt hypertension

作者：Gao, Ying; Liu, Benquan; Guo, Xiaoqing; Nie, Jiayi; Zou, Hao; Wen, Shihong; Yu, Wenqiang; Liang, Hua^*

来源：Journal of Hypertension, 2023, 41(5): 794-810.

DOI：10.1097/HJH.0000000000003401

• hypertension nephropathy
• interferon regulatory factor 4
• macrophage

Background:Inflammation and renal interstitial fibrosis are the main pathological features of hypertensive nephropathy. Interferon regulatory factor 4 (IRF-4) has an important role in the pathogenesis of inflammatory and fibrotic diseases. However, its role in hypertension-induced renal inflammation and fibrosis remains unexplored.Method and results:We showed that deoxycorticosterone acetate (DOCA)-salt resulted in an elevation of blood pressure and that there was no difference between wild-type and IRF-4 knockout mice. IRF-4(-/-) mice presented less severe renal dysfunction, albuminuria, and fibrotic response after DOCA-salt stress compared with wild-type mice. Loss of IRF-4 inhibited extracellular matrix protein deposition and suppressed fibroblasts activation in the kidneys of mice subjected to DOCA-salt treatment. IRF-4 disruption impaired bone marrow-derived fibroblasts activation and macrophages to myofibroblasts transition in the kidneys in response to DOCA-salt treatment. IRF-4 deletion impeded the infiltration of inflammatory cells and decreased the production of proinflammatory molecules in injured kidneys. IRF-4 deficiency activated phosphatase and tensin homolog and weakened phosphoinositide-3 kinase/AKT signaling pathway in vivo or in vitro. In cultured monocytes, TGF & beta;1 also induced expression of fibronectin and & alpha;-smooth muscle actin and stimulated the transition of macrophages to myofibroblasts, which was blocked in the absence of IRF-4. Finally, macrophages depletion blunted macrophages to myofibroblasts transition, inhibited myofibroblasts accumulation, and ameliorated kidney injury and fibrosis.Conclusion:Collectively, IRF-4 plays a critical role in the pathogenesis of kidney inflammation and fibrosis in DOCA-salt hypertension.

• 单位
  佛山市第一人民医院; 广东医学院; 中山大学; 1; 南方医科大学