The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids

Debelle, Frédéric; Nortier, Joëlle; Husson, Cécile; Prez, Eric G. De; Vienne, Anne; Rombaut, Katja; Salmon, Isabelle; Deschodt-Lanckman, M; Vanherweghem, Jean‐Louis

doi:10.1111/j.1523-1755.2004.00905.x

Cited by 35 publications

(24 citation statements)

References 49 publications

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“…At present, angiotensinconverting enzyme inhibitors and angiotensin II receptor type 1 blockers are clinically used to combat renal fibrosis (Locatelli et al, 2009;Morrow et al, 2010). However, these drugs are not able to completely stop the progression of renal fibrosis; in some conditions, such as aristolochic acid-induced renal fibrosis in rats, they are not effective at all (Debelle et al, 2004;Boor et al, 2007). Because renal fibrogenesis is a complex process that is involved in the activation of multiple cellular and molecular mediators, the incomplete antifibrotic effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor type 1 blockers may be due to their limited targets.…”

Section: Introductionmentioning

confidence: 99%

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Liu

Tolbert²,

Ponnusamy³

et al. 2011

J Pharmacol Exp Ther

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We recently showed that suramin treatment prevents the onset of renal fibrosis in a model of obstructive nephropathy induced by unilateral ureteral obstruction (UUO). In this study, we further assessed the effect of delayed administration of suramin on the progression of tubulointerstitial fibrosis. Mice were given a single dose of suramin at 20 mg/kg starting at day 3 of obstruction, and kidneys were harvested after an additional 7 or 14 days of obstruction. Suramin completely blocked further increase in expression of type I collagen and fibronectin and largely suppressed expression of ␣-smooth muscle actin (␣-SMA) in both treatment groups. UUO injury induced phosphorylation of Smad-3, a key mediator of transforming growth factor-␤ (TGF-␤) signaling, epidermal growth factor receptor, and platelet-derived growth factor receptor after 3 days and further increased at 10 days after UUO injury. When suramin was administered at 3 days after obstruction, phosphorylation of these molecules was not further increased in the obstructed kidney. Suramin treatment also inhibited activation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1 and 2, two signaling pathways associated with renal fibrogenesis. Furthermore, delayed application of suramin suppressed TGF-␤1-induced expression of ␣-SMA and fibronectin in cultured renal interstitial fibroblasts. These results indicate that administration of suramin is effective in attenuating the progression of renal fibrosis after injury and suggest the potential clinical application of suramin as an antifibrotic treatment in patients with chronic kidney disease.

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Section: Introductionmentioning

confidence: 99%

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Liu

Tolbert²,

Ponnusamy³

et al. 2011

J Pharmacol Exp Ther

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show abstract

“…Up to now, therapeutic strategies have been mainly conservative when renal insufficiency is detected [10] . Angiotensin-converting enzyme inhibitors did not modify the evolution of the renal disease [28] . Previous studies have investigated possible mechanisms of AA-induced nephrotoxicity both in vitro and in vivo and have suggested the role of AAI-induced apoptosis in renal tubular cells through either the endoplasmic reticulum (ER) stress pathway or the mitochondrial cell death pathway [29,30] .…”

Section: Discussionmentioning

confidence: 83%

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

Xiao

Xue

et al. 2009

Acta Pharmacol Sin

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Aim:The role of CYP1A in the protection of aristolochic acid (AA)I-induced nephrotoxicity has been suggested. In the present study we investigated the effects of β-naphthoflavone (BNF), a non-carcinogen CYP1A inducer, on AAI-induced kidney injury. Methods: Mice were pretreated with 80 mg/kg BNF by daily intraperitoneal injection (ip) for 3 days followed by a single ip of 10 mg/kg AAI. AAI and its major metabolites in blood, liver and kidney, the expression of CYP1A1 and CYP1A2 in microsomes of liver and kidney, as well as the nephrotoxicity were evaluated. Results: BNF pretreatment prevented AAI-induced renal damage by facilitating the disposal of AAI in liver. BNF pretreatment induced the expression of CYP1A1 in both liver and kidney; but the induction of CYP1A2 was only observed in liver. Conclusion: BNF prevents AAI-induced kidney toxicity primarily through CYP1A induction.

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“…13,14 There have been many hypothesizes about the pathogenesis of acute AAN. Some researchers found that there was blood vessel injury in AAN, 4,7,8,15 and they thought it could be one of the causes for the continuously progressing tubulointerstitial damage.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Prostaglandin E1 on Renal Microvascular Injury in Rats of Acute Aristolochic Acid Nephropathy

Sun

Liu

et al. 2011

Renal Failure

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Background: To investigate the renal microvascular injury in acute aristolochic acid nephropathy (AAN) and the protective effects of prostaglandin E1 (PGE1) in acute AAN. Methods: Female Sprague-Dawley rats were randomly divided into three groups. The rats in PGE1 group received Caulis Aristolochia manshuriensis (CAM) decoction by gavage for 5 days, and PGE1 was given by vena caudalis before gavage. The rats in model group were gavaged with CAM for 5 days, and the same dose of 0.9% physiologic saline was given by vena caudalis. The rats in control group only received an equal daily volume of saline solution by gavage. Animals were killed at days 3, 5, and 7. Blood urea nitrogen (BUN), serum creatinine, and urinary protein were monitored before killing. Microvascular density was determined by JG12 immunostaining. The expression of angiogenic factor was assessed by vascular endothelial growth factor (VEGF). Tubulointerstitial hypoxia was assessed by hypoxia-inducible factor-1a (HIF-1a) expression. Results: CAM induced a significant decrease in VEGF expression and microvascular density in the kidney tissue, accompanied by a significant increase in HIF-1a, which reduced renal function and increased 24-h urinary protein excretion rates. PGE1 lessened the capillary loss, relieved hypoxia, and protected renal function. No significant pathological changes were found in control rats. Conclusion: The renal microvascular injury in acute AAN is severe. PGE1 can significantly ameliorate the renal microvascular injury, relieve hypoxia, and protect renal function.

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The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids

Abstract: Our data demonstrate that RAS modulation by salt depletion and pharmacologic blockade do not influence renal failure and interstitial fibrosis in the rat model of AAN. We suggest that pathways of interstitial renal fibrosis may be independent of RAS at least in some conditions.

Cited by 35 publications

References 49 publications

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

Delayed Administration of Suramin Attenuates the Progression of Renal Fibrosis in Obstructive Nephropathy

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

Protective Effect of Prostaglandin E1 on Renal Microvascular Injury in Rats of Acute Aristolochic Acid Nephropathy

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