AT<sub>1A</sub>-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan

Davis, Ann M.; Padda, Ranjit S.; Truong, Luan D.; Tsao, Chun C.; Zhang, Ping; Sheikh-Hamad, David

doi:10.1152/ajprenal.00452.2003

Cited by 25 publications

(19 citation statements)

References 44 publications

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“…AT 1 blockade downregulated Smad2 protein and activity and attenuated the chronic tubulointerstitial injury in obstructed kidneys. 9 These data indicate that Smad signaling could be a common mechanism of Ang II-mediated fibrosis in cardiovascular and renal diseases. The activation of the Smad signaling pathway causes nuclear translocation of Smads.…”

Section: Discussionmentioning

confidence: 89%

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Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism

Rodríguez-Vita¹,

Sánchez-López²,

Esteban³

et al. 2005

Circulation

300

267

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Background— Angiotensin II (Ang II) participates in vascular fibrosis. Transforming growth factor-β (TGF-β) is considered the most important fibrotic factor, and Smad proteins are essential components of the TGF-β signaling system. Our aim was to investigate whether Ang II activates the Smad pathway in vascular cells and its potential role in fibrosis, evaluating connective tissue growth factor (CTGF) and extracellular matrix (ECM) proteins. Methods and Results— Systemic infusion of Ang II into Wistar rats increased aortic Smad2, phosphorylated-Smad2, and Smad4 expression, associated with CTGF upregulation. In growth-arrested vascular smooth muscle cells, Ang II treatment for 20 minutes caused Smad2 phosphorylation, nuclear translocation of phosphorylated-Smad2 and Smad4, and increased Smad DNA-binding activity. Ang II also caused Smad overexpression and Smad-dependent gene transcription. The AT 1 antagonist losartan diminished Ang II-induced Smad activation. The blockade of endogenous TGF-β did not modify the activation of Smad caused by Ang II. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 diminished Ang II-induced Smad2 phosphorylation. These data show that Ang II activates the Smad pathway via AT 1 receptors and MAPK activation independently of TGF-β. Transient transfection with Smad7, which interferes with receptor-mediated activation of Smad2, diminished Ang II-induced CTGF promoter activation, gene and protein expression, and fibronectin and type-1 procollagen overexpression, showing that Smad activation is involved in Ang II-induced fibrosis. Conclusions— Our results show that Ang II activates the Smad signaling system in vascular cells in vivo and in vitro. Smad proteins are involved in Ang II-induced CTGF and ECM overexpression independently of TGF-β. This novel finding suggests that Smad activation could be involved in the profibrogenic effects of Ang II in vascular diseases.

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Section: Discussionmentioning

confidence: 89%

“…1,3,[5][6][7] AT 1 blockade diminishes Smad pathway activation in myocardial infarction in rats and in an experimental model of renal damage. 8,9 However, no studies have investigated whether Ang II activates the Smad signaling pathway in VSMCs and its potential role in vascular fibrosis.…”

mentioning

confidence: 99%

Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism

Rodríguez-Vita¹,

Sánchez-López²,

Esteban³

et al. 2005

Circulation

300

267

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“…86 Administration of an angiotensin AT1 receptor inhibitor reduces c-Jun-N-terminal kinase (JNK1) activity and downregulates Smad2 activity in rats with UUO. 87 Interestingly, whereas HGF gene therapy alone reduces UUO-induced myofibroblast accumulation by 50%, combined HGF gene therapy and angiotensin AT1 receptor inhibition completely abolishes induction of α-smooth muscle actin and synergistically inhibits accumulation of collagen I. 88 The phenotypic transformation of fibroblasts to myofibroblasts involves upregulation of the early growth response gene 1 (Egr-1).…”

Section: Interstitial Fibrosismentioning

confidence: 99%

Obstructive nephropathy: towards biomarker discovery and gene therapy

2006

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Obstructive nephropathy is a major cause of renal failure, particularly in infants and children. Cellular and molecular mechanisms responsible for the progression of the tubular atrophy and interstitial fibrosis-processes that lead to nephron loss-have been elucidated in the past 5 years. Following urinary tract obstruction and tubular dilatation, a cascade of events results in upregulation of the intrarenal renin-angiotensin system, tubular apoptosis and macrophage infiltration of the interstitium. This is followed by accumulation of interstitial fibroblasts through proliferation of resident fibroblasts and epithelial-mesenchymal transformation of renal tubular cells. Under the influence of cytokines, chemokines and other signaling molecules produced by tubular and interstitial cells, fibroblasts undergo transformation to myofibroblasts that induce expansion of the extracellular matrix. The cellular interactions that regulate development of interstitial inflammation, tubular apoptosis and interstitial fibrosis are complex. Changes in renal gene expression and protein production afford many potential biomarkers of disease progression and targets for therapeutic manipulation. These include signaling molecules and receptors involved in macrophage recruitment and proliferation, tubular death signals and survival factors, and modulators of epithelial-mesenchymal transformation. Targeted gene deletion and various forms of gene therapy have been used in experimental obstructive nephropathy, mostly rodent models of unilateral ureteral obstruction or cell culture techniques. Further refinement of these models is needed to develop a matrix of biomarkers with clinical predictive value, as well as molecular therapies that will prevent or reverse the renal structural and functional consequences of obstructive nephropathy.

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“…In addition, Moriyama et al (31) found that the ANG II receptor antagonist TCV-116 ameliorates the interstitial fibrosis and the progression of morphological changes in rat kidneys in response to complete UUO. Other studies have also shown that AT 1 -receptor blockade improved tubulointerstitial fibrosis in rats subjected to UUO (18,47).Inflammatory cell infiltration plays a key role in the onset and progression of renal injury in response to obstruction. Nuclear factor-B participates in the inflammatory response, regulating many proinflammatory genes.…”

mentioning

confidence: 90%

Candesartan prevents long-term impairment of renal function in response to neonatal partial unilateral ureteral obstruction

Topçu

Pedersen²,

Nørregaard³

et al. 2007

American Journal of Physiology-Renal Physiology

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Angiotensin II (ANG II) plays an important role in the development of obstructive nephropathy. Here, we examined the effects of the ANG II receptor type 1 (AT1R) blockade using candesartan on long-term renal molecular and functional changes in response to partial unilateral ureteral obstruction (PUUO). Newborn rats were subjected to severe PUUO or sham operation (Sham) within the first 48 h of life. Candesartan was provided in the drinking water (10 mg.kg(-1).day(-1)) from day 21 of life until 10 wk of age. Renal blood flow (RBF) was evaluated by MRI, glomerular filtration rate (GFR) was measured using the renal clearance of (51)Cr-EDTA, and the renal expression of Na-K-ATPase and the collecting duct water channel aquaporin-2 (AQP2) was examined by immunoblotting and immunocytochemistry. At 10 wk of age, PUUO significantly reduced RBF (0.8 +/- 0.1 vs. 1.6 +/- 0.1 ml.min(-1).100 g body wt(-1); P < 0.05) and GFR (37 +/- 16 vs. 448 +/- 111 microl.min(-1).100 g body wt(-1); P < 0.05) compared with Sham. Candesartan prevented the RBF reduction (PUUO+CAN: 1.6 +/- 0.2 vs. PUUO: 0.8 +/- 0.1 ml.min(-1).100 g body wt(-1); P < 0.05) and attenuated the GFR reduction (PUUO+CAN: 265 +/- 68 vs. PUUO: 37 +/- 16 microl.min(-1).100 g body wt(-1); P < 0.05). PUUO was also associated with a significant downregulation in the expression of Na-K-ATPase (75 +/- 12 vs. 100 +/- 5%, P < 0.05) and AQP2 (52 +/- 15 vs. 100 +/- 4%, P < 0.05), which were also prevented by candesartan (Na-K-ATPase: 103 +/- 8 vs. 100 +/- 5% and AQP2: 74 +/- 13 vs. 100 +/- 4%). These findings were confirmed by immunocytochemistry. Consistent with this, candesartan treatment partly prevented the reduction in solute free water reabsorption and attenuated fractional sodium excretion in rats with PUUO. In conclusion, candesartan prevents or attenuates the reduction in RBF, GFR and dysregulation of AQP2 and Na-K-ATPase in response to congenital PUUO in rats, suggesting that AT1R blockade may protect the neonatally obstructed kidney against development of obstructive nephropathy.

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AT_1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan

Cited by 25 publications

References 44 publications

Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism

Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism

Obstructive nephropathy: towards biomarker discovery and gene therapy

Candesartan prevents long-term impairment of renal function in response to neonatal partial unilateral ureteral obstruction

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

Cited by 25 publications

References 44 publications

Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism

Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism

Obstructive nephropathy: towards biomarker discovery and gene therapy

Candesartan prevents long-term impairment of renal function in response to neonatal partial unilateral ureteral obstruction

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Product

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AT_1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan