Losartan modulation on NOS isoforms and COX-2 expression in early renal fibrogenesis in unilateral obstruction.
BACKGROUND
Angiotensin II plays a central role in the initiation of renal fibrogenesis at a very early stage leading to a rapid progression in unilateral ureteral obstruction (UUO). We examined the effect of an angiotensin II receptor inhibitor (AT(1)) losartan, independent from its effects on blood pressure, on nitric oxide synthase (NOS) isoforms and cyclooxygenase-2 (COX-2) expression and the significance of this interaction on interstitial fibrosis in UUO.


METHODS
Rats underwent UUO for 24 hours or control sham operation after been treated with losartan in the drinking water at 10 mg/kg/day for 15 days. AT(1) receptor binding and distribution was determined by in situ autoradiographic study. Renal fibrosis was evaluated through the relative volume of the tubulointerstitium (Vv) measured by an image analyzer, and transforming growth factor-beta (TGF-beta) at mRNA levels. NOS activity, expression of NOS isoforms by reverse transcription-polymerase chain reaction (RT-PCR) assay and COX-2 protein expression, were determined.


RESULTS
After administration of a nonhypotensive dose of losartan prevention of renal fibrogenesis was demonstrated in obstructed kidneys by means of Vv values and TGF-beta mRNA expression near controls. Decreased AT(1) receptor binding density was observed in cortex and inner stripe of the outer medulla of nontreated obstructed kidney compared to control, whereas no differences were observed in ipsilateral UUO related to obstructed kidney-treated group. The increased inducible NOS (iNOS) activity and expression of obstructed kidney medulla, increased neuronal NOS (nNOS), and endothelial NOS (eNOS) isoforms expression and COX-2 protein expression in obstructed kidney cortex showed down-regulation of iNOS, nNOS, and COX-2 with persistent levels of eNOS after losartan administration.


CONCLUSIONS
These results allowed us to infer an interstitial fibrogenesis prevention independent action of losartan, involving NOS isoforms and COX-2, in unilateral obstructive nephropathy.
Manucha
Walter
W
Cátedra de Fisiopatología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza, Argentina. wmanucha@fmed2.uncu.edu.ar
Oliveros
Liliana
L
Carrizo
Liliana
L
Seltzer
Alicia
A
Vallés
Patricia
P
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D051546:Cyclooxygenase 2; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D019808:Losartan / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007527:Isoenzymes; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016212:Transforming Growth Factor beta; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019808:Losartan