ABSTRACT
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)-α has been addressed in preserving kidney function during AKI. Among endogenous lipid mediators, oleoylethanolamide (OEA), a PPAR-α 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 α-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)-ß1, fibronectin, and collagen IV. Mechanistically, the nephroprotective effect of OEA was related to PPAR-α activation since OEA failed to exert its beneficial activity in FA-insulted PPAR-α-/- mice. PPAR-α involvement was also confirmed in HK2 cells where GW6471, a PPAR-α antagonist, blunted OEA activity on the TGF-ß1 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.
Subject(s)
Acute Kidney Injury , Endocannabinoids , Oleic Acids , Renal Insufficiency, Chronic , Mice , Animals , PPAR alpha , Kidney , Acute Kidney Injury/pathology , Fibrosis , Inflammation/pathology , Transforming Growth Factor beta1/metabolism , Renal Insufficiency, Chronic/pathologyABSTRACT
El tejido graso presenta una intensa actividad metabólica derivada de la síntesis y la secreción de hormonas relacionadas con el metabolismo energético y con acciones directas sobre la estructura y la función del corazón y del sistema cardiovascular en su conjunto. Desde el descubrimiento de la leptina, se ha identificado un conjunto de adipocitocinas producidas sobre todo por el tejido graso, pero también por otros tejidos. Destacan la síntesis y la secreción de estas hormonas por los cardiomiocitos, en cuyas estructura y metabolismo ejercen efectos directos. La grasa epicárdica constituye una parte importante de la grasa visceral, con una intensa actividad metabólica. Este compartimento graso presenta, respecto a la grasa subcutánea, una menor expresión deadiponectina y mayor de interleucinas, relacionadas con la extensión de la enfermedad coronaria y la presencia de hipertensión arterial. Las adipocinas constituyen una familia de hormonas con importantes acciones en el sistema cardiovascular. En particular, se relacionan con la aterotrombosis y podrían constituir una nueva diana terapéutica en la reducción del riesgo cardiovascular (AU)
Adipose tissue exhibits a high level of metabolic activity that stems from the synthesis and secretion of hormones associated with energy metabolism. These hormones have a direct effect on the structure and function of the heart and on the cardiovascular system as a whole. Since the discovery of leptin, a group of adipokines produced mainly by adipose tissue, but also by other tissues, has been identified. Interestingly, these adipokines may also be synthesized and secreted by cardiomyocytes, and they have a direct influence on cardiomyocyte structure and metabolism. Epicardial fat is an important part of visceral fat and has a high level of metabolic activity. Compared with subcutaneous fat, this fat compartment expresses less adiponectin but more interleukins, and itis linked to the severity of coronary artery disease and the presence of hypertension. The adipokines form a family of hormones whose actions exert significant effects on the cardiovascular system. In particular, they are associated with a the rothrombosis and could provide a new therapeutic target for reducing cardiovascular risk (AU)