N-Palmitoylethanolamide protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress

Abstract

Hypertension is an important risk factor for kidney failure and renal events in the general population. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with profound analgesic and anti-inflammatory effects, resulting from its ability to activate peroxisome proliferator activated receptor (PPAR)α. A role for this nuclear receptor has been addressed in cardiovascular system and PPARα ligands have been shown to protect against inflammatory damage especially resulting from angiotensin II hypertension. In this study, we demonstrated that PEA significantly reduced blood pressure in spontaneously hypertensive rats (SHR) and limited kidney damage secondary to high perfusion pressure. To investigate the mechanisms involved in PEA effect, we found that PEA reduced cytochrome P450 (CYP) hydroxylase CYP4A, epoxygenase CYP2C23 and soluble epoxide hydrolase enzyme expression in the kidney, accompanied by a reduction of 20-hydroxyeicosatetraenoic acid excretion in the urine. Moreover, it markedly reduced kidney oxidative and nitrosative stress accompanied by decreased expression of renal NAD(P)H oxidase and inducible nitric oxide synthase and increased expression of Cu/Zn superoxide dismutase, in the kidney of SHR. Moreover, angiotensin II receptor (AT) evaluation revealed a decrease in AT1 receptor expression and a restoration of AT2 receptor level in the kidney from PEA-treated SHR. Consistently, angiotensin converting enzyme expression was reduced, implying a decrease in angiotensin II synthesis. These results indicate that PEA treatment lowers blood pressure and can protect against hypertensive renal injury by increasing the antioxidant defense and anti-inflammatory response and modulating renin-angiotensin system.

Keywords: AA; ACE; AT; Ang II; Angiotensin II; Angiotensin receptors; CYP; EET; Epoxyeicosatrienoic acid; GFR; HETE; HR; Hydroxyeicosatetraenoic acid; Hypertension; Oxidative stress; PEA; PPAR; PPRE; Palmitoylethanolamide; RAAS; RNS; ROS; Renal damage; SBP; SHR; SOD; WKY; Wistar Kyoto; angiotensin converting enzyme; angiotensin receptor; arachidonic acid; cytochrome P-450; epoxyeicosatrienoic acid; glomerular filtration rate; heart rate; hydroxyeicosatetraenoic acid; iNOS; inducible nitric oxide synthase; palmitoylethanolamide; peroxisome proliferator response elements; peroxisome proliferator-activated receptor; reactive nitrogen species; reactive oxygen species; renin-angiotensin aldosterone system; sEH; soluble epoxide hydrolase; spontaneously hypertensive rats; superoxide dismutase; systolic blood pressure.