High Endogenous Accumulation of ω-3 Polyunsaturated Fatty Acids Protect against Ischemia-Reperfusion Renal Injury through AMPK-Mediated Autophagy in Fat-1 Mice

Abstract

Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). Fat-1 transgenic mice produce ω3-Polyunsaturated fatty acids (ω3-PUFAs) from ω6-Polyunsaturated fatty acids (ω6-PUFAs) without a dietary ω3-PUFAs supplement, leading to a high accumulation of omega-3 in various tissues. ω3-PUFAs show protective effects against various renal injuries and it has recently been reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated its associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham (n = 10), fat-1 sham (n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI (n = 15). Kidneys and blood were harvested 24 h after IRI and renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7; lower amounts of p62; and, higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more adenosine monophosphate-activated protein kinase (AMPK) activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.

Omega-3 multiple effects increasing glucocorticoid-induced muscle atrophy: autophagic, AMPK and UPS mechanisms

“…), renal tissue (ischemia‐reperfusion study) (Gwon et al. ), immune system/macrophages (Shen et al. ), central nervous systems (CNS)/microglia (Inoue et al.…”

Protective Effects of ω-3 PUFA in Anthracycline-Induced Cardiotoxicity: A Critical Review

“…Moreover, in a future prospective, it should be emphasized that, although the mechanisms of cytotoxicity related to the oxidative stress are those mainly investigated by the ATC/ω-3 PUFA combined studies, recently, several other important and more specific mechanisms have been sought to explain the health effects of ω-3 PUFA, both in general and at CV levels ( Figure 1 ). Some of them involve their anti-inflammatory activities, as well as their ability to negatively modulate some molecular pathways, such as those leading to the activation of NF-κB or those involved in autophagy [ 126 , 127 , 128 , 129 ], or to influence the epigenetic regulation [ 7 , 130 ]. Interestingly, these mechanisms represent some of those more recently involved in the ATC-induced cardiotoxicity.…”

Autophagy Function and Regulation in Kidney Disease

“…AMPK activators (5-aminoimidazol-4-carboxamide-1-β-d-ribofuranoside and metformin) have been shown to protect against IR, and inhibition of AMPK with compound C has been shown to worsen kidney injury [94]. Many other natural agents, including quercetin [95], omega 3-polyunsaturated fatty acid (PUFA) [96], and pioglitazone [97], afforded protection from renal IR through AMPK-mediated autophagy. Enhancing autophagy through the AMPK/mTOR-mediated pathway also provided protection against cisplatin-induced nephrotoxicity.…”