Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway

Abstract

Background Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive. Methods We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration. Results We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity. Conclusions Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.

Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics

“…Hederasaponin C, a natural product, effectively inhibits lipopolysaccharide (LPS)-induced acute kidney injury in mice by specifically targeting Toll-like receptor 4 (TLR4) and modulating the phosphatidylinositol 4,5-bisphosphate (PIP2)/NF-κB/NLRP3 signaling pathway [ 254 ]. Spermidine, another natural molecule, protects against kidney injury by downregulating NLRP3 inflammasome activation and IL-1β production in renal macrophages [ 255 ]. Fisetin, a flavonoid, ameliorates renal fibrosis in the UUO mice model by inhibiting Smad3 phosphorylation [ 256 ].…”

The Molecular Mechanism and Therapeutic Strategy of Cardiorenal Syndrome Type 3

“…Maadawy, Walaa H et al [96] found that 6-Paradol alleviates diclofenac induced AKI by regulating autophagy enhancement mediated by AMP-activated protein kinases/AKT kinase/mammalian target of rapamycin (AMPK/AKT/mTOR) and the NLRP3 inflammasome pathway. Li et al [97] found that spermidine improved AKI by inhibiting the activation of the NLRP3 mediatedinflammasome in macrophages. Collectively, these studies provide evidence that inhibition of inflammasome activation could improve AKI.…”

Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma

“…Spermidine, synthesized by putrescine and S-adenosylmethionine, exhibits multiple biological functions, including cell differentiation, proliferation, angiogenesis, gene expression, anti-aging, anti-inflammatory, and anticancer activities (Madeo et al, 2018;Pegg, 2014). Specifically, spermidine can prevent sepsis-induced acute kidney injury by downregulating the Nod-like receptor family pyrin domain containing 3 inflammasomes and interleukin-1β in macrophages (Li et al, 2022). Furthermore, spermidine can improve the function of human cells and delay aging (Madeo et al, 2018;Wang et al, 2020;Xu et al, 2020).…”