Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury.
The role of the angiotensin type 2 (AT(2)) receptor in the pathogenesis of progressive renal injury has not been previously elucidated. The renal expression of the AT(1) and AT(2) receptors in subtotally nephrectomized rats (STNx) and the effects of AT(2) receptor blockade on renal injury were explored. Reduced renal expression of the AT(1) but not the AT(2) receptor was observed in STNx by reverse transcription-PCR, by in vitro autoradiography, and by immunohistochemical staining. The STNx rats were randomly assigned to AT(1) receptor antagonist valsartan, AT(2) receptor antagonist PD123319, or the combination of both for 4 wk. Increased proteinuria in STNx rats was reduced by PD123319 but to a lesser degree when compared with valsartan. Reduced gene and protein expression of the slit diaphragm protein nephrin was prevented by either valsartan or PD123319. Expression of osteopontin, proliferating cell nuclear antigen, and monocyte/macrophage infiltration was increased in STNx rats and was reduced by both AT(1) and AT(2) receptor antagonists. These effects of AT(2) receptor antagonism were observed in the presence of increased BP in STNx rats. These findings suggest that blockade of the AT(2) receptor alone confers a degree of renal protection; in particular, it seems that the combination of the AT(1) and AT(2) receptor antagonists may confer additive renal effects than either receptor antagonist as monotherapy.
Cao
Zemin
Z
Department of Medicine, Austin & Repatriation Medical Centre (Repatriation Campus), University of Melbourne, Heidelberg West, Victoria 3081, Australia. cao@austin.unimelb.edu.au
Bonnet
Fabrice
F
Candido
Riccardo
R
Nesteroff
Stefan P
SP
Burns
Wendy C
WC
Kawachi
Hiroshi
H
Shimizu
Fujio
F
Carey
Robert M
RM
De Gasparo
Marc
M
Cooper
Mark E
ME
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019610:Cytoprotection; D004231:Diuresis / Q000187:drug effects; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins; D009392:Nephrectomy / Q000379:methods; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D008565:Membrane Proteins; D011506:Proteins; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C113267:nephrin; C073402:PD 123319; D000068756:Valsartan; D014633:Valine