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

[摘要]：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 proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone 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 gamma agonist rosiglitazone, the PPAR alpha ligands fenofibrate and clofibrate significantly increased survival (p < 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p < 0.001) and delaying increased proteinuria (p < 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 beta, transforming growth factor beta, 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 alpha agonists was at least partially caused by their anti-inflammatory 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 alpha agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

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