Different protective actions of losartan and tempol on the renal inflammatory response to acute sodium overload.
The aim of this work was to study the role of local intrarenal angiotensin II (Ang II) and the oxidative stress in the up-regulation of pro-inflammatory cytokines expression observed in rats submitted to an acute sodium overload. Sprague-Dawley rats were infused for 2 h with isotonic saline solution (Control group) and with hypertonic saline solution alone (Na group), plus the AT1 receptor antagonist losartan (10 mg kg(-1) in bolus) (Na-Los group), or plus the superoxide dismutase mimetic tempol (0.5 mg min(-1) kg(-1)) (Na-Temp group). Mean arterial pressure, glomerular filtration rate, and fractional sodium excretion (FE(Na)) were measured. Ang II, NF-kappaB, hypoxia inducible factor-1 alpha (HIF-1 alpha), transforming growth factor beta1 (TGF-beta1), smooth muscle actin (alpha-SMA), endothelial nitric oxide synthase (eNOS), and RANTES renal expression was evaluated by immunohistochemistry. Ang II, NF-kappaB, and TGF-beta1 and RANTES early inflammatory markers were overexpressed in Na group, accompanied by enhanced HIF-1 alpha immunostaining, lower eNOS expression, and unmodified alpha-SMA. Losartan and tempol increased FE(Na) in sodium overload group. Although losartan reduced Ang II and NF-kappaB staining and increased eNOS expression, it did not restore HIF-1 alpha expression and did not prevent inflammation. Conversely, tempol increased eNOS and natriuresis, restored HIF-1 alpha expression, and prevented inflammation. Early inflammatory markers observed in rats with acute sodium overload is associated with the imbalance between HIF-1 alpha and eNOS expression. While both losartan and tempol increased natriuresis and eNOS expression, only tempol was effective in restoring HIF-1 alpha expression and down-regulating TGF-beta1 and RANTES expression. The protective role of tempol, but not of losartan, in the inflammatory response may be associated with its greater antioxidant effects.
Rosón
María I
MI
School of Pharmacy and Biochemistry, Department of Pathophysiology, Pharmacology and Clinical Biochemistry, University of Buenos Aires, INFIBIOC, CONICET, Buenos Aires, Argentina. iroson@ffyb.uba.ar
Della Penna
Silvana L
SL
Cao
Gabriel
G
Gorzalczany
Susana
S
Pandolfo
Marcela
M
Toblli
Jorge E
JE
Fernández
Belisario E
BE
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D009393:Nephritis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012462:Saline Solution, Hypertonic; D013113:Spin Labels; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014883:Water-Electrolyte Imbalance / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology
D000199:Actins; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D018946:Chemokine CCL5; D003497:Cyclic N-Oxides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D019808:Losartan; D016328:NF-kappa B; D052250:Nitric Oxide Synthase Type III; D012462:Saline Solution, Hypertonic; D013113:Spin Labels; D053773:Transforming Growth Factor beta1; C497444:Hif1a protein, rat; C498862:Acta2 protein, rat; C496316:Nos3 protein, rat; C001803:tempol