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Peroxisome proliferator-activated receptor (PPAR)-α has been implicated in the regulation of normal and pathological cellular functions, but the effect of specific gene silencing on PPARα-mediated function is not fully defined.This study evaluated the role of PPARα in hypertensive renal injury induced by nitric oxide withdrawal and high salt (4% NaCl) diet [high salt/Nω-nitro-L-arginine (L-NNA)].Three PPARα siRNA clones, siRNA790–811, siRNA974–995 or siRNA1410–1431, directed at the DNA or ligand binding domain of PPARα mRNA or scrambled siRNA was cloned into plasmid expression vector and was injected (10 μg intravenously) in hypertensive rats. Twenty-four-hour readings of blood pressure and heart rate were taken in conscious rats using radiotelemetry. Kidney injury was evaluated by determining N-acetyl-β-glucosaminidase excretion, expression of kidney injury molecule-1 and histopathology. PPARα mRNA and protein expression were also determined.High salt/L-NNA increased PPARα mRNA expression three-fold, and this was abolished in rats treated with PPARα siRNA790–811, siRNA974–995 or siRNA1410–1431. High salt/L-NNA also increased blood pressure but reduced heart rate without affecting pulse pressure. However, blood pressure was further increased in rats treated with PPARα siRNA790-811 (37 ± 3%, P < 0.05). High salt/L-NNA also increased N-acetyl-β-glucosaminidase excretion and expression of kidney injury molecule-1. However, PPARα siRNA790–811 did not affect N-acetyl-β-glucosaminidase excretion but reduced kidney injury molecule-1 expression. Histopathology of kidney tissues in high salt/L-NNA-treated rats revealed global, fibrinoid and tubular interstitial necrosis that was blunted by PPARα siRNA790–811.These data suggest that increased PPARα expression is a protective mechanism in hypertensive renal injury induced by nitric oxide withdrawal/high salt diet and that siRNAs targeting the DNA-binding domain of PPARα gene elicited differential effects on hypertension and kidney injury.