Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence

Abstract

ObjectiveContinuous 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.MethodsRenal 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. In vitro, cellular senescence was induced in renal proximal tubular epithelial cell lines (TKPTS cells) by treatment with norepinephrine (NE). The selective α2A-adrenergic receptor (α2A-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.ResultsRenal fibrosis and cellular senescence were significantly increased in UUO and UIRI models, which were partially reversed by renal denervation. In vitro, NE induced epithelial cells secreting proinflammatory cytokines and promoted cell senescence by activating α2A-AR. Importantly, the effects of NE during cellular senescence were blocked by α2A-AR selective antagonist and β-arrestin2 (downstream of α2A-AR) siRNA.ConclusionRenal sympathetic activation and cellular senescence are important neurometabolic and neuroimmune mechanisms in the development of renal fibrosis. Renal sympathetic neurotransmitter NE acting on the α2A-AR of epithelial cells promotes cellular senescence through the downstream β-arrestin2 signaling, which is a potential preventive target for renal fibrosis.

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

“…4,5 Enhanced renal sympathetic nerve traffic has also been implicated in the progression of chronic kidney disease, in part related to the stimulation of intrarenal angiotensin II and in part related to the activation of α-2 adrenoreceptors, which may play a role in the pathogenesis of renal interstitial inflammation and fibrosis. 6,7 Renal denervation produces favorable effects in experimental HF and renal disease and improves cardiac function in the clinical setting. [4][5][6][7][8][9] Of note, although they are generally characterized as inhibitors of the sympathetic nervous system, β-blockers do not reduce renal sympathetic nerve traffic.…”

“…6,7 Renal denervation produces favorable effects in experimental HF and renal disease and improves cardiac function in the clinical setting. [4][5][6][7][8][9] Of note, although they are generally characterized as inhibitors of the sympathetic nervous system, β-blockers do not reduce renal sympathetic nerve traffic. 10…”

Myocardial infarction with a preserved ejection fraction—the impaired function of the cardio-renal baroreflex

“…Others demonstrated recently that sympathetic denervation led to amelioration of renal fibrosis and of cellular senescence in a model of unilateral ureteral obstruction and a model of unilateral ischemia-reperfusion injury. Interestingly, the cellular senescence of renal proximal tubular epithelial cell lines was mediated by a selective α2A-adrenergic receptor in vitro ( Li et al, 2022 ). These findings provide clues to the possible neurometabolic and neuroimmune mechanisms that could explain the increase of renal collagen due to impaired control of renal sympathetic nerve activity.…”

Cellular senescence in ischemia/reperfusion injury

“…These studies emphasize the importance of inflammation microenvironment in cellular senescence. Meanwhile, Qian Li et al pointed out that renal sympathetic neurotransmitter NE, acting on the α 2A -AR of epithelial cells, could promote the crosstalk between inflammation and cellular senescence, contributing to renal fibrosis after IR injury [ 54 ]. Weifeng Yao et al found that aerosol inhalation of a hydrogen-rich solution would attenuate renal macrophage infiltration, the release of pro-inflammatory cytokine, and cellular senescence via TGF-β1 pathway in septic acute kidney injury (AKI) [ 55 ].…”