Losartan modulation on NOS isoforms and COX-2 expression in early renal fibrogenesis in unilateral obstruction

WALTER MANUCHA; LILIANA OLIVEROS; LILIANA CARRIZO; ALICIA SELTZER; PATRICIA G. VALLES

KIDNEY INTERNATIONAL

Nature Publishing Group

Lugar: New York; Año: 2004 vol. 65 p. 2091 - 2107

0085-2538

Background: Angiotensin II plays a central role in the initiation of renal fibrogenesis at a very early stage leading to a rapid progression, in UUO. We examined the effect of an AT1 angiotensin II receptor inhibitor Losartan, independent from its effects on blood pressure, on NOS isoforms and COX-2 expression and the significance of this interaction on interstitial fibrosis in OUU. Methods: Rats underwent UUO for 24 h or control sham operation after been t reated with Losartan in the drinking water at 10 mg/Kg/day for 15 days. AT1 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 TGF-B 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 non-hypotensive dose of Losartan prevention of renal fibrogenesis was demonstrated in obstructed kidneys (Oks) by means of Vv values and TGF-B mRNA expression near controls. Decreased AT1 receptor binding density was observed in cortex and inner stripe of the outer medulla of non- treated OK compared to control, whereas no differences were observed in ipsilateral UUO related to OK treated group. The increased iNOS activity and expression of OK medulla, increased nNOS and eNOS isoforms expression and COX-2 protein expression in OK cortex showed, downregulation of iNOS, nNOS and COX-2 with persistent levels of eNOS after Losartan administration. These results allowed us to infer an interstitial fibrogenesis prevention independent action of Losartan, involving NOS isoforms and COX-2, in unilateral obstructive nephropathy.1 angiotensin II receptor inhibitor Losartan, independent from its effects on blood pressure, on NOS isoforms and COX-2 expression and the significance of this interaction on interstitial fibrosis in OUU. Methods: Rats underwent UUO for 24 h or control sham operation after been t reated with Losartan in the drinking water at 10 mg/Kg/day for 15 days. AT1 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 TGF-B 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 non-hypotensive dose of Losartan prevention of renal fibrogenesis was demonstrated in obstructed kidneys (Oks) by means of Vv values and TGF-B mRNA expression near controls. Decreased AT1 receptor binding density was observed in cortex and inner stripe of the outer medulla of non- treated OK compared to control, whereas no differences were observed in ipsilateral UUO related to OK treated group. The increased iNOS activity and expression of OK medulla, increased nNOS and eNOS isoforms expression and COX-2 protein expression in OK cortex showed, downregulation of iNOS, nNOS and COX-2 with persistent levels of eNOS after Losartan administration. These results allowed us to infer an interstitial fibrogenesis prevention independent action of Losartan, involving NOS isoforms and COX-2, in unilateral obstructive nephropathy.