Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis.
Cellular and molecular events contributing to tubulointerstitial fibrosis of the kidney during obstructive nephropathy are driven in large part through increased angiotensin II levels in the obstructed kidney. Angiotensin converting enzyme inhibition or AT1 receptor antagonism have been shown to ameliorate the fibrosis of the kidney due to obstruction of the ureter. In this investigation, we determine the effects of the AT2 receptor antagonist PD-123319 on pathophysiological events within the kidneys of rats with unilateral ureteral obstruction. Treatment with PD-123319 was found to exacerbate the increase in interstitial volume and collagen IV matrix score of the ureteral obstructed kidney. Monocyte/macrophage infiltration of the injured kidney was no different between treated and untreated animals. The AT2 receptor antagonist did, however, inhibit apoptosis of tubular cells, alpha-smooth muscle actin expression within the interstitium, and p53 expression in the ureteral obstructed kidney. These results suggest that angiotensin II operating through the AT2 receptor exerts an antifibrotic effect on the kidney during obstructive nephropathy in opposition to the profibrotic effects of angiotensin II operating through the AT1 receptor.
Morrissey
J J
JJ
Renal Division of the Department of Internal Medicine, and the Department of Cell Biology-Physiology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
Klahr
S
S
D000199:Actins / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D009130:Muscle, Smooth / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
D000199:Actins; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D016159:Tumor Suppressor Protein p53; C073402:PD 123319