TY - JOUR
T1 - Effect of peroxisome proliferator-activated receptor-α siRNA on hypertension and renal injury in the rat following nitric oxide withdrawal and high salt diet
AU - Newaz, Mohammad
AU - Ranganna, Katsuri
AU - Truong, Luan D.
AU - Oyekan, Adebayo
PY - 2009/11
Y1 - 2009/11
N2 - Background 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. Aim 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)]. Methods Three PPARα siRNA clones, siRNA 790-811, 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. Results 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 siRNA 790-811 (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. Conclusion 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.
AB - Background 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. Aim 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)]. Methods Three PPARα siRNA clones, siRNA 790-811, 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. Results 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 siRNA 790-811 (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. Conclusion 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.
KW - Blood pressure
KW - High salt diet
KW - Kidney injury molecule-1
KW - N-acetyl-β- glucosaminidase
KW - Peroxisome proliferator-activated receptorα
KW - siRNA
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U2 - 10.1097/HJH.0b013e328330b6d9
DO - 10.1097/HJH.0b013e328330b6d9
M3 - Article
C2 - 19834340
AN - SCOPUS:73249123240
SN - 0263-6352
VL - 27
SP - 2223
EP - 2231
JO - Journal of Hypertension
JF - Journal of Hypertension
IS - 11
ER -