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)-β in the renal injury that follows chronic ureteric obstruction. SMAD proteins and the JNK1 cascade are essential components of TGF-β signaling machinery, and recent data suggest cooperative interaction between JNK1 and SMAD proteins in TGF-β-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, 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 AT1A-receptor blockade in obstructive uropathy are consistent with attenuation of JNK1- and SMAD2-mediated renal injury.

obstruction of urine flow complicates many human diseases, such as prostate hypertrophy, abdominopelvic malignancies, and retroperitoneal fibrosis. It is characterized by infiltration of mononuclear inflammatory cells, predominantly macrophages, and is accompanied by activation of cytokines, growth factors, and mediators of apoptosis, the net result of which is the deletion of tubular cells by apoptosis and replacement of renal parenchyma with fibrous tissue. If left untreated, chronic kidney obstruction leads to loss of functional renal parenchyma, and ultimately, the development of kidney failure. Numerous reports implicate the renin-angiotensin system in the pathogenesis of ureteric obstruction, and inhibition of the rennin-angiotensin system, using either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, has been shown to attenuate the renal injury that follows ureteric obstruction (19, 23, 37). Activation of the kidney renin-angiotensin system occurs immediately after urteric obstruction, with resultant vasoconstriction and salt and water retention (14). These hemodynamic changes are followed by the activation of a number of cytokines (6, 9, 20, 21, 36, 50), some of which have been directly linked to angiotensin II, such as monocyte chemotactic protein-1 (MCP-1) (20) and transforming growth factor-β (TGF-β) (22), which appears to play a key role in the genesis of the ensuing fibrosis (32). TGF-β signaling is initiated after ligand binding to the TGF-β receptor (15, 33), leading to phosphorylation of SMAD2 or SMAD3 (1, 47, 53). SMAD proteins represent a group of transcription factors involved in gene regulation downstream of the TGF-β receptor. A heteromeric SMAD proteins complex is formed (7), resulting in translocation of the complex to the nucleus (1, 31, 47), where it can interact with transcription factors directly (7), or indirectly (27), to regulate gene expression. It was recently reported that JNK pathway (25, 51), which targets the activation of c-Jun and activated transcription factor-2 (ATF-2) (8, 12, 16, 26), is stimulated rapidly by TGF-β in human fibrosarcoma cells and that JNK activity is essential for TGF-β-induced fibronectin production (17). Furthermore, it was also suggested that SMAD proteins and the JNK1 pathway interact cooperatively in TGF-β signaling (17). These observations assume particular importance, in light of recent data that implicate JNK1 in the development of cell apoptosis after ischemia and UV irradiation in a variety of tissues (2, 3). Apoptosis is a crucial component in the pathogenesis of ureteric obstruction (5, 49). Based on these observations, we hypothesized that JNK1 may be a key contributor to the development of renal injury and fibrosis in obstructive uropathy, and thus renal protection after AT1A-receptor blockade in obstructive uropathy may be related to the downregulation of JNK1 and SMAD proteins. Consistent with this hypothesis, our data suggest activation of SMAD2 and JNK1 signaling in obstructed kidneys in a manner that is AT1A dependent. AT1A- receptor blockade using candesartan downregulates JNK1 and SMAD2, decreases tissue fibrosis, and leads to tissue preservation in obstructed kidneys.