title: Activation of renal angiotensin type 1 receptor contributes to the pathogenesis of progressive renal injury in a rat model of chronic cardiorenal syndrome.
abstract: Although chronic cardiac dysfunction is known to progressively exacerbate renal injury, a condition known as type 2 cardiorenal syndrome (CRS), the mechanism responsible is largely unknown. The present study was undertaken to clarify the mechanism of renal injury in rats with both unilateral nephrectomy (NX) and surgically induced myocardial infarction (MI), corresponding to a model of type 2 CRS. Compared with a control group, rats with both MI and NX (MI+NX) exhibited progressive proteinuria during the experimental period (34 wk after MI surgery), whereas proteinuria was not observed in rats with MI alone and was moderate in rats with NX alone. The proteinuria in rats with MI+NX was associated with renal lesions such as glomerulosclerosis and infiltration of mononuclear cells and upregulation of the renal proinflammatory and -fibrotic cytokine and angiotensin II type 1a receptor (AT1aR) genes. In contrast, plasma renin activity was lowered in rats with MI+NX. Immunohistochemistry revealed that the increased AT1R protein was present mainly in renal interstitial mononuclear cells. Olmesartan medoxomil, an AT1R blocker, markedly reduced the proteinuria and infiltration of mononuclear cells, whereas spironolactone, a mineralocorticoid receptor blocker, did not. The present findings demonstrate the pathogenetic role of renal interstitial AT1R signaling in a model of type 2 CRS, providing evidence that AT1R blockade can be a useful therapeutic option for this syndrome.
authors.affiliation: Department of Veterinary Pharmacology, Faculty of Agriculture, Univ. of Miyazaki, Gakuenkibanadai-Nishi 1-1, Miyazaki 889-2192, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Homma
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sonoda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Manabe
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Arai
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.forename: Toshio
authors.initials: T
authors.lastname: Sada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D059347:Cardio-Renal Syndrome / Q000378:metabolism*; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009203:Myocardial Infarction; D009392:Nephrectomy; D000068557:Olmesartan Medoxomil; D011507:Proteinuria; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000097:blood / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013148:Spironolactone; D000068557:Olmesartan Medoxomil; D012083:Renin