Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence

• Published in: Frontiers in immunology 2022-01, Vol.12, p.823935-823935
• Main Authors: Li, Qian, Deng, Yuanjun, Liu, Lele, Zhang, Chunjiang, Cai, Yang, Zhang, Tianjing, Han, Min, Xu, Gang
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; cellular senescence; Cellular Senescence - genetics; Cellular Senescence - immunology; Cytokines - metabolism; Disease Models, Animal; Disease Susceptibility; Energy Metabolism; Fibrosis; Gene Expression Regulation; Immunohistochemistry; Immunology; Inflammation Mediators - metabolism; Kidney Diseases - etiology; Kidney Diseases - metabolism; Kidney Diseases - pathology; Mice; Mitochondria - genetics; Mitochondria - metabolism; neuroimmune; neurometabolic; Receptors, Adrenergic, alpha-2 - genetics; Receptors, Adrenergic, alpha-2 - metabolism; renal fibrosis; Signal Transduction; Sympathectomy - adverse effects; sympathetic denervation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.823935

Continuous overactivation of the renal sympathetic nerve is considered to be an important cause of renal fibrosis. Accumulated senescent cells in the damaged kidney have metabolic activities and secrete amounts of proinflammatory factors as part of the SASP (the senescence-associated secretory phenotype), which induce chronic inflammation and fibrosis. It is still unclear whether renal sympathetic nerves affect renal inflammation and fibrosis by regulating cellular senescence. Therefore, we hypothesize that sympathetic activation in the injured kidney induces cellular senescence, which contributes to progressive renal inflammation and fibrosis. Renal denervation was performed 2 days before the UUO (unilateral ureteral obstruction) and UIRI (unilateral ischemia-reperfusion injury) models. The effects of renal denervation on renal fibrosis and cellular senescence were observed. , cellular senescence was induced in renal proximal tubular epithelial cell lines (TKPTS cells) by treatment with norepinephrine (NE). The selective α -adrenergic receptor (α -AR) antagonists BRL44408 and β-arrestin2 siRNA, were administered to inhibit NE-induced cellular senescence. A significantly altered pathway was identified through immunoblotting, immunofluorescence, immunocytochemistry, and functional assays involved in mitochondrial function. Renal fibrosis and cellular senescence were significantly increased in UUO and UIRI models, which were partially reversed by renal denervation. , NE induced epithelial cells secreting proinflammatory cytokines and promoted cell senescence by activating α -AR. Importantly, the effects of NE during cellular senescence were blocked by α -AR selective antagonist and β-arrestin2 (downstream of α -AR) siRNA. Renal sympathetic activation and cellular senescence are important neurometabolic and neuroimmune mechanisms in the development of renal fibrosis. Renal sympathetic neurotransmitter NE acting on the α -AR of epithelial cells promotes cellular senescence through the downstream β-arrestin2 signaling, which is a potential preventive target for renal fibrosis.