Submitted on December 5, 2006
Accepted on February 28, 2007
AT1 receptor blockade prevents interstitial and glomerular apoptosis but not fibrosis in pigs with neonatal induced partial unilateral ureteral obstruction
Anni Eskild-Jensen1, Lene Fogt Paulsen2, Lise Wogensen3, Ping Olesen3, Lea Pedersen3, Jorgen Frokiaer4*, and Jens Randel Nyengaard2
1 Department of Clinical Physiology, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark
2 Stereology and Electron Microscopy Research Laboratory and MIND Center, University of Aarhus, Aarhus, Denmark
3 Research Laboratory of Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark
4 The Water and Salt Research Center, University of Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: jf{at}ki.au.dk.
Obstruction-induced fibrosis is a leading cause of end-stage renal failure in children. The pathophysiological mechanisms may involve apoptosis and the renin-angiotensin system. We studied apoptosis and fibrosis in a well-established neonatal pig model with unilateral partial ureteral obstruction (PUUO) induced during ongoing nephrogenesis in 2-day-old piglets. The role of angiotensin II (ANGII) was studied using the AT1 receptor blocker CV-11974 (0.12 mg/h candesartan from age 23 to 30 days). At day 30 the kidneys were perfusion fixed and fibrosis, apoptosis and tubular lengths quantitated using stereological methods, picro Sirius red staining, and immunohistochemical techniques identifying activated caspase 3, aquaporin 2 (AQP2), and von Willebrand factor. The collagen content was assessed by hydroxyproline density. Neonatal induced PUUO increased interstitial and glomerular cell apoptosis and fibrosis. At this stage PUUO did not increase tubular cell apoptosis or decrease tubular length and cell-number. AT1 receptor blockade prevented the PUUO-induced interstitial and glomerular cell apoptosis but did not attenuate fibrosis. In conclusion AT1 receptor blockade after end of nephrogenesis may prevent interstitial and glomerular cell apoptosis but not fibrosis, suggesting that pathways not involving AT1 receptor stimulation contribute to neonatal obstruction-induced fibrosis or that prevention of interstitial cell apoptosis counteracts a potential anti-fibrotic effect of AT1 receptor blockade in this pig model of congenital obstructive nephropathy. Our results demonstrate that ANG II plays a role in PUUO-induced glomerular cell apoptosis.
