Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption

Abstract

Cytochrome P450 2E1 (CYP2E1) induction and oxidative metabolism of ethanol in hepatocytes inflames and damages liver. Chronic ethanol ingestion also induces kidney dysfunction, which associates with mortality of alcoholic hepatitis. Whether kidney is directly affected by ethanol or is secondary to liver damage is not established. We found CYP2E1 was induced in kidney tubules of mice chronically ingesting a modified Lieber-deCarli liquid ethanol diet. Phospholipids of kidney tubules were oxidized and fragmented in ethanol fed mice with accumulation of azelaoyl phosphatidylcholine (Az-PC), a non-biosynthetic product formed only by oxidative truncation of polyunsaturated phosphatidylcholine. Az-PC stimulates the inflammatory PAF receptor (PTAFR) abundantly expressed by neutrophils and kidney tubules, and inflammatory cells and myeloperoxidase-containing neutrophils accumulated in kidney of ethanol fed mice after significant hysteresis. Decreased kidney filtration and induction of the Acute Kidney Injury biomarker KIM-1 in tubules temporally correlated with leukocyte infiltration. Genetic ablation of PTAFR reduced accumulation of PTAFR ligands, and reduced leukocyte infiltration into kidney. Loss of this receptor in PTAFR−/− mice also suppressed oxidative damage and kidney dysfunction without affecting CYP2E1 induction. Neutrophilic inflammation was responsible for ethanol-induced kidney damage because loss of neutrophil myeloperoxidase in MPO−/− mice was similarly protective. We conclude ethanol catabolism in renal tubules results in a self-perpetuating cycle of CYP2E1 induction, local PTAFR ligand formation, neutrophil infiltration and activation that leads to myeloperoxidase-dependent oxidation and damage to kidney function. Hepatocytes do not express PTAFR, so this oxidative cycle is a local response to ethanol catabolism in kidney.

Protective Effect of Taurine on Thiopurine-Induced Testicular Atrophy in Male Albino Rats

“…The anti-inflammatory action of TAU, evidenced in the current study, confirms previous findings of [54], who demonstrated the effective role of TAU as an antiinflammatory supplement when given to alleviate the inflammation induced in the kidney by chronic ethanol ingestion.…”

Enhanced Platelet-Activating Factor Synthesis Facilitates Acute and Delayed Effects of Ethanol-Intoxicated Thermal Burn Injury

“…In particular, chronic ethanol administration in rats and mice results in increased levels of oxidized GPCs and PAF in plasma (Liu et al, 2013;Yang et al, 2010). Moreover, PAF-Redeficient mice are protected from chronic ethanol-mediated kidney damage (Latchoumycandane et al, 2015). In these chronic ethanol models, nonenzymatic oxidized GPC PAF agonists appear to play important roles, whereas the present acute ethanol and thermal injury model involves enzymatic PAF agonists.…”

Effect of imidazoline‐1 receptor agonists on renal dysfunction in rats associated with chronic, sequential fructose and ethanol administration

“…Additionally, Grossmann et al observed a state of low‐grade inflammation in insulin‐resistant patients . Previous research showed that ethanol‐fed rats have significantly decreased renal catalase, SOD and glutathione levels and increased MDA, MPO and inflammatory mediator levels …”

“…Chronic alcoholism induces expression of the ethanol metabolising enzyme cytochrome P450 2E1 (CYP2E1), particularly in the kidneys . This enzyme modifies phospholipids in cell membranes, which activates neutrophil granulocytes and aggravates oxidative stress …”