AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan.
Literature suggests the involvement of the renin-angiotensin system and transforming growth factor (TGF)-beta in the renal injury that follows chronic ureteric obstruction. SMAD proteins and the JNK1 cascade are essential components of 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 AT(1A)-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, and marked activation of SMAD2 and JNK1, without significant change in p38 kinase or ERK. 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 downregulated 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 AT(1A)-receptor blockade in obstructive uropathy are consistent with attenuation of JNK1- and SMAD2-mediated renal injury.
Wamsley-Davis
Ann
A
Renal Section, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Padda
Ranjit
R
Truong
Luan D
LD
Tsao
Chun Chui
CC
Zhang
Ping
P
Sheikh-Hamad
David
D
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051899:Smad2 Protein; D013777:Tetrazoles / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D044140:Receptor, Angiotensin, Type 1; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D013777:Tetrazoles; D015534:Trans-Activators; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C081643:candesartan