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J Hypertens. 2009 Nov;27(11):2223-31. doi: 10.1097/HJH.0b013e328330b6d9.

Effect of peroxisome proliferator-activated receptor-alpha siRNA on hypertension and renal injury in the rat following nitric oxide withdrawal and high salt diet.

Author information

1
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, USA.

Abstract

BACKGROUND:

Peroxisome proliferator-activated receptor (PPAR)-alpha has been implicated in the regulation of normal and pathological cellular functions, but the effect of specific gene silencing on PPARalpha-mediated function is not fully defined.

AIM:

This study evaluated the role of PPARalpha in hypertensive renal injury induced by nitric oxide withdrawal and high salt (4% NaCl) diet [high salt/N(omega)-nitro-L-arginine (L-NNA)].

METHODS:

Three PPARalpha siRNA clones, siRNA(790-811), siRNA(974-995) or siRNA(1410-1431), directed at the DNA or ligand binding domain of PPARalpha mRNA or scrambled siRNA was cloned into plasmid expression vector and was injected (10 microg 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-beta-glucosaminidase excretion, expression of kidney injury molecule-1 and histopathology. PPARalpha mRNA and protein expression were also determined.

RESULTS:

High salt/L-NNA increased PPARalpha mRNA expression three-fold, and this was abolished in rats treated with PPARalpha siRNA(790-811), siRNA(974-995) or siRNA(1410-1431). 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 PPARalpha siRNA(790-811) (37 +/- 3%, P < 0.05). High salt/L-NNA also increased N-acetyl-beta-glucosaminidase excretion and expression of kidney injury molecule-1. However, PPARalpha siRNA(790-811) did not affect N-acetyl-beta-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 PPARalpha siRNA(790-811).

CONCLUSION:

These data suggest that increased PPARalpha 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 PPARalpha gene elicited differential effects on hypertension and kidney injury.

PMID:
19834340
DOI:
10.1097/HJH.0b013e328330b6d9
[Indexed for MEDLINE]

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