Oleoylethanolamide attenuates acute-to-chronic kidney injury: in vivo and in vitro evidence of PPAR-α involvement

被引：8

作者：

Comella, Federica ^{[1
]}

Lama, Adriano ^{[1
]}

Pirozzi, Claudio ^{[1
]}

Annunziata, Chiara ^{[1
]}

Piegari, Giuseppe ^{[2
]}

Sodano, Federica ^{[1
]}

Melini, Stefania ^{[1
]}

Paciello, Orlando ^{[2
]}

Paz, Francisca Lago ^{[3
]}

Meli, Rosaria ^{[1
]}

Raso, Giuseppina Mattace ^{[1
,4
]}

机构：

[1] Univ Naples Federico II, Sch Med, Dept Pharm, I-80131 Naples, Italy

[2] Univ Naples Federico II, Dept Vet Med & Anim Prod, I-80137 Naples, Italy

[3] Univ Clin Hosp Santiago de Compostela, Santiago De Compostela 15706, Spain

[4] Dept Pharm, Via Domen Montesano 49, I-80131 Naples, Italy

来源：

BIOMEDICINE & PHARMACOTHERAPY | 2024年 / 171卷

关键词：

Chronic kidney disease; Renal fibrosis; N-acylethanolamines; Peroxisome proliferator-activated receptor; Epithelial-mesenchymal transition; Extracellular matrix; EXPRESSION; FIBROSIS; CELLS; BIOMARKERS; OXIDATION; AGONISTS; REPERFUSION; ACTIVATION; MECHANISMS; PROTECTION;

D O I：

10.1016/j.biopha.2023.116094

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Chronic kidney disease (CKD) development after acute kidney injury (AKI) involves multiple mechanisms, including inflammation, epithelial-mesenchymal transition (EMT), and extracellular matrix deposition, leading to progressive tubulointerstitial fibrosis. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-alpha has been addressed in preserving kidney function during AKI. Among endogenous lipid mediators, oleoylethanolamide (OEA), a PPAR-alpha agonist, has been studied for its metabolic and anti-inflammatory effects. Here, we have investigated OEA effects on folic acid (FA)-induced kidney injury in mice and the underlying mechanisms. OEA improved kidney function, normalized urine output, and reduced serum BUN, creatinine, and albuminuria. Moreover, OEA attenuated tubular epithelial injury, as shown by histological analysis, and decreased expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Gene expression analysis of kidney tissue indicated that OEA limited immune cell infiltration and inflammation. Moreover, OEA significantly inhibited Wnt7b and Catnb1 gene transcription and alpha-smooth muscle actin expression, indicating suppression of EMT. Accordingly, OEA exhibited an anti-fibrotic effect, as shown by Masson staining and the reduced levels of transforming growth factor (TGF)-beta 1, fibronectin, and collagen IV. Mechanistically, the nephroprotective effect of OEA was related to PPAR-alpha activation since OEA failed to exert its beneficial activity in FA-insulted PPAR-alpha-/- mice. PPAR-alpha involvement was also confirmed in HK2 cells where GW6471, a PPAR-alpha antagonist, blunted OEA activity on the TGF-beta 1 signalling pathway and associated pro-inflammatory and fibrotic patterns. Our findings revealed that OEA counteracts kidney injury by controlling inflammation and fibrosis, making it an effective therapeutic tool for limiting AKI to CKD progression.

引用

页数：13

共 66 条

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