Peroxisome Proliferator-Activated Receptor α Agonism Prevents Renal Damage and the Oxidative Stress and Inflammatory Processes Affecting the Brains of Stroke-Prone Rats

Abstract

A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferatoractivated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive strokeprone rats (SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPAR␥ agonist rosiglitazone, the PPAR␣ ligands fenofibrate and clofibrate significantly increased survival (p Ͻ 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p Ͻ 0.001) and delaying increased proteinuria (p Ͻ 0.001). Fenofibrate completely prevented the renal disorder characterized by severe vascular lesions, tubular damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1␤, transforming growth factor ␤, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPAR␣ agonists was at least partially caused by their antiinflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPAR␣ agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

RETRACTED ARTICLE: Effect of preischemic treatment with fenofibrate, a peroxisome proliferator-activated receptor-α ligand, on hepatic ischemia–reperfusion injury in rats

“…Proliferation of peroxisomes in hepatocytes is induced, at least in part, by activation of the transcription factor PPARa (Clark 2002). PPARa activation prevents cell damage, the oxidative stress and inflammatory processes (Gelosa et al 2010).…”

“…The PPARa agonist, fenofibrate, supports multiple cellular functions and plays a key role in the protection from oxidative stress induced injury (Gelosa et al 2010;Hou et al 2010). So, fenofibrate exerts an antioxidant, anti-inflammatory and anti-ischemic protective effect on the brain (Chen et al 2007) and kidney (Bhalodia et al 2010).…”

Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes

“…Since PPARα ligands showed anti-oxidative stress properties in previous studies (36,37,45), one of the mechanisms by which the drug silafibrate may protect rat hepatocytes against acetaminophen might be its effect Nafisi S, et on alleviating oxidative stress (Figure 4). The effect of silafibrate on lipid peroxidation induced by acetaminophen could be attributed to its effect on reducing the ROS level, which is a major cause of lipid peroxidation in cells (46).…”

“…However, the mechanism(s) underlying the hepatoprotection afforded by peroxisome proliferators have yet to be clarified, but the induction of antioxidant enzymes (34), alteration in cellular glutathione content (35), and protection against oxidative stress and inflammatory responses (36)(37)(38) are the proposed protective mechanisms. It has been found that PPAR ligands have a role in modulating oxidative stress and its deleterious consequences in different tissues such as liver (39), nervous (40), and vascular systems (41).…”

Proteomics of rat biological fluids — The tenth anniversary update

“…valsartan, an angiotensin II type 1 receptor antagonist [10], pentoxifylline, a nonspecific type 4 phosphodiesterase inhibitor [9], rosuvastatin, a hydrophilic competitive inhibitor of HMG-CoA reductase [11], terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist [107], fenofibrate, a peroxisome proliferatoractivated receptor α agonist [108]) also drastically reduce the levels of circulating APR (and chiefly of thiostatin) as well as the loss of proteins in urine.…”