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Am J Physiol Renal Physiol (May 4, 2004). doi:10.1152/ajprenal.00452.2003
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Submitted on December 29, 2003
Accepted on April 21, 2004

AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: Preservation of kidney tissue mass using Candesartan

Ann Wamsley-Davis1, Ranjit Padda1, Luan D. Truong2, Chun Chui Tsao2, Ping Zhang2, and David Sheikh-Hamad1*

1 Department of Medicine, Baylor College of Medicine, Houston, TX, USA
2 Department of Pathology, Baylor College of Medicine, Houston, TX, USA

* To whom correspondence should be addressed. E-mail: sheikh{at}bcm.tmc.edu.

Literature data suggest the involvement of the renin angiotensin system and TGF-{beta} in the renal injury that follows chronic ureteric obstruction. SMAD proteins and Jun N-terminal kinase (JNK1) cascade are essential components of transforming growth factor-beta (TGF-{beta}) signaling machinery, and recent data suggest cooperative interaction between JNK1 and SMAD proteins in TGF-{beta}-mediated gene expression. We used a rat model of chronic unilateral ureteric obstruction, to study the effects of Candesartan, an AT1A receptor blocker, on tissue morphology, and the activities of JNK1 and SMAD2 protein in the kidney. Ureteric obstruction for 28 days leads to interstitial fibrosis, tubule atrophy, marked activation of SMAD2 and JNK1, without significant change in p38 kinase or ERK (Extracellular Regulated Kinase). Candesartan treatment, however, attenuated the chronic tubulointerstitial injury in obstructed kidneys and was associated with significant preservation of kidney tissue mass. Furthermore, treatment with Candesartan diminished JNK1 activity and down regulated SMAD2 protein and activity in obstructed kidneys. In conclusion, obstructed kidneys showed chronic tubulointerstitial injury, which was associated with JNK1 and SMAD2 activation. The renoprotective effects afforded by AT1A receptor blockade in obstructive uropathy, are consistent with attenuation of JNK1- and SMAD2-mediated renal injury.




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