Angiotensin AT₁-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat

Abstract

Coleman CM, Minor JJ, Burt LE, Thornhill BA, Forbes MS, Chevalier RL. Angiotensin AT1-receptor inhibition exacerbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat. Am J Physiol Renal Physiol 293: F262-F268, 2007. First published April 18, 2007; doi:10.1152/ajprenal.00071.2007.-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 AT2 to AT1 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 (AT1 inhibitor), or PD-123319 (AT2 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, ␣-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, ␣-smooth muscle actin, and collagen in the obstructed kidney. Early losartan treatment further increased ␣-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 AT1 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.hydronephrosis; nephrogenesis; apoptosis; ␣-smooth muscle actin; collagen CONGENITAL URINARY TRACT OBSTRUCTION is a major cause of chronic renal insufficiency in infants and children (43). Despite intrauterine diagnosis and prompt evaluation and management of the neonate, the combination of fetal urinary tract maldevelopment and the consequences of urinary obstruction on the developing kidney lead to renal injury that is present even at the time of birth. Prevention of progression of renal injury in these infants is even more critical than in older patients with renal disorders.The renin-angiotensin system (RAS) has been shown to play a significant role in the progression of virtually all renal disorders, and pharmacological inhibition of angiotensin II is a widely accepted therapy for attenuating or preventing renal deterioration. Since the RAS is activated to a greater extent neonatally than at older ages, and urinary tract obstruction itself markedly activates the RAS, the rationale for angiotensin II inhibition in this set...

How the Kidney Is Impacted by the Perinatal Maternal Environment to Develop Hypertension1

“…Despite these promising effects, it is important to emphasize that ACE inhibitors and AT 1 R antagonists are potential teratogenic agents to humans [134,135] and thus, their use is contraindicated during pregnancy. Caveats include the numerous studies demonstrating that the use of RAS inhibitors program adverse effects when administered prenatally in the rat [122,[136][137][138]] as compared to their action when administered after weaning [120,131,133]. Taken together, PAIXÃ O AND ALEXANDER these studies indicate early lifestyle changes including antioxidant supplementation, a balanced diet, salt restriction, or even therapeutic maneuvers can serve as potential targets and may prove effective in counteracting the adverse programming of chronic health in the event that adverse environmental influences during development cannot be avoided.…”

Mechanisms of renal injury and progression of renal disease in congenital obstructive nephropathy

“…Angiotensin inhibition in young or adult rats with UUO improves long-term renal function after release of the obstruction [75,76], but as discussed below, angiotensin inhibition during UUO in the postnatal period actually aggravates obstructive injury [77,78]. Renal blood flow is determined by the balance between vasoconstrictors and vasodilators, and thromboxanes contribute to the reduction in glomerular filtration rate in rats with congenital unilateral hydronephrosis [79].…”

“…From reference [57], with permission nephropathy. While this has been borne out by the salutary renal effects of enalapril administered to 3-week-old rats with UUO [75], the administration of enalapril or losartan to younger rats with UUO actually aggravates the renal lesions [77,78]. This is because adequate levels of intrarenal angiotensin are necessary for normal renal development [114].…”

Long-term effects of neonatal drugs on the kidney

“…Postnatal administration of AT1-receptor antagonist (7 mg/kg/day) in rats, from day 1 to day 14, impaired the renal response to an increment of plasma aminoacid concentrations and the kidneys' ability to eliminate an acute volume expansion [6]. A selective inhibition with the AT1-receptor blocker losartan (10 mg/kg/day) during active nephrogenesis in rats (but not during subsequent renal maturation) exacerbated the injury to both obstructed kidney and normal contra-lateral kidney [7].…”