Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence

Abstract

Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.

Cellular senescence: the good, the bad and the unknown

“…Emerging evidence indicates that senescence contributes to the progression of AKI and that senescence inhibition can promote kidney recovery. For example, inhibition of tubular cell senescence using lipoxin A4 restored renal function in a rat model of septic shock-induced AKI 173 . Similarly, in a rat model of contrast-induced AKI, pre-treatment with paricalcitol before contrast medium administration reduced cellular senescence (that is, expression of SABG and p16 INK4A ) and tissue damage and prevented kidney dysfunction 174 .…”

Melatonin Alleviates Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis

“…Recently, some novel mechanisms have been found involved in AKI. Chen et al found that crosstalk between connexin 32 and mitochondrial apoptotic signaling pathway plays a pivotal role in renal ischemia reperfusion-induced AKI and lipoxin A4 restores septic renal function via blocking crosstalk between inflammation and premature senescence [ 25 , 26 ]. Yuan et al reported that gap junction composed of Cx43 inhibition attenuated RIP1 and MLKL expression via mediating the content of ROS and then prevented acute kidney injury following liver transplantation [ 27 ].…”

Cellular senescence and acute kidney injury

“…LXA4 pretreatment significantly restores kidney function and improves the survival rate of rats after cecal ligation and puncture (CLP). LXA4 inhibits NF-kappa B (NF/kB)–mediated inflammation and the p53/p21 senescence pathway in a PPAR-γ-dependent manner to alleviate kidney inflammation and renal TEC senescence [ 87 ]. Nicotinamide mononucleotide (NMN), when administered in advance or during the recovery phase, can reduce senescence and fibrosis in H 2 O 2 and hypoxia kidney injury, and ischemia–reperfusion-AKI mice [ 88 ].…”