Angiotensin AT1-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat.
The renin-angiotensin system is activated in the developing kidney and is necessary for normal renal development, but is further activated by unilateral ureteral obstruction (UUO). During nephrogenesis, there is a switch from a preponderance of angiotensin AT(2) to AT(1) receptors in the rat. We examined the renal cellular response to angiotensin II receptor inhibition in the neonatal rat subjected to partial UUO under anesthesia within 48 h of birth. Group I ("early") received saline vehicle, losartan (AT(1) inhibitor), or PD-123319 (AT(2) inhibitor) during the completion of nephrogenesis in the first 10 days of life. Group II ("late") received each of the three treatments throughout the subsequent 10 days of life. Kidneys were harvested at 21 days, and the distribution of renin, apoptosis, macrophages, alpha-smooth muscle actin, and collagen was determined. Losartan and PD-123319 each increased vascular renin distribution in both kidneys. Partial UUO reduced growth and increased apoptosis, macrophages, alpha-smooth muscle actin, and collagen in the obstructed kidney. Early losartan treatment further increased alpha-smooth muscle actin and collagen in the obstructed kidney and induced apoptosis, macrophages, and collagen in the contralateral kidney. Late losartan treatment had no effect on any of the parameters in either kidney, and PD-123319 had no effect on either kidney. We conclude that selective inhibition of AT(1) receptors during nephrogenesis (but not during subsequent renal maturation) exacerbates injury to the obstructed kidney and also injures the contralateral kidney. These results suggest that angiotensin II receptor blockers should be avoided in the developing hydronephrotic kidney.
Coleman
Christopher M
CM
Dept. of Pediatrics, University of Virginia, Box 800386, Charlottesville VA 22908, USA.
Minor
Jordan J
JJ
Burt
Laura E
LE
Thornhill
Barbara A
BA
Forbes
Michael S
MS
Chevalier
Robert L
RL
D000375:Aging / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000633:toxicity*; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology*; D019808:Losartan / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000150:complications*
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D003094:Collagen; D012964:Sodium; D019808:Losartan