Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule

Tayem, Yasin; Johnson, Tony; Mann, Brian E.; Green, Colin J.; Motterlini, Roberto

doi:10.1152/ajprenal.00363.2005

Cited by 115 publications

(98 citation statements)

References 33 publications

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“…37 In addition, CO releasing molecules have also been successfully tested for cytoprotection in cisplatin-mediated cell injury. 38 Therefore, we can not definitely rule out that effects other than HIF stabilization contribute to the in the protective effect of CO observed in our experiments.…”

Section: Discussionmentioning

confidence: 71%

HIF Activation Protects From Acute Kidney Injury

Weidemann¹,

Bernhardt²,

Klanke³

et al. 2008

Journal of the American Society of Nephrology

160

124

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The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1␣ protein in vitro or in vivo under normoxic conditions. However, hypoxic preconditioning of cisplatin-treated proximal tubular cells in culture reduced apoptosis in an HIF-1␣-dependent fashion and increased cell proliferation as measured by BrdU incorporation. In vivo, rats preconditioned with carbon monoxide before cisplatin administration had significantly better renal function than rats kept in normoxic conditions throughout. Moreover, the histomorphological extent of renal damage and tubular apoptosis was reduced by the preconditional treatment. Therefore, development of pharmacologic agents to induce renal HIF might provide a new approach to ameliorate cisplatin-induced nephrotoxicity.

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Section: Discussionmentioning

confidence: 71%

HIF Activation Protects From Acute Kidney Injury

Weidemann¹,

Bernhardt²,

Klanke³

et al. 2008

Journal of the American Society of Nephrology

160

124

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“…HO-1 overexpression or CO administration has been shown to protect experimental kidney transplants from ischemia-reperfusion injury (4,30). Moreover, the administration of CO donor compounds, namely carbon monoxide-releasing molecules (CORM-3), protected against cisplatin nephrotoxicity and ischemia-reperfusion-induced renal injury (44,47). A recent report also demonstrated that hemin, a chemical inducer of HO-1, decreased renal injury and interstitial fibrosis in UUO (18).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

Wang¹,

Lee²,

Kwak³

et al. 2008

American Journal of Physiology-Renal Physiology

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Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of α-smooth muscle actin (α-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-β1-induced expression of α-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.

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“…A watersoluble, CO-releasing molecule (CORM-3) (Clark et al, 2003;Motterlini et al, 2005) was used as a source of exogenous CO to assess the contribution of this HO product on oxidant-mediated toxicity. In a control experiment, an inactive form of CORM-3 (iCORM-3) that is not capable of releasing CO was used as described before (Clark et al, 2003;Motterlini et al, 2005;Tayem et al, 2006). Cell viability was expressed as a percentage of the optical density in untreated cells from three experiments carried out in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Effectiveness of Novel Imidazole-Dioxolane Heme Oxygenase Inhibitors in Renal Proximal Tubule Epithelial Cells

Kinobe¹,

Ji²,

Vlahakis³

et al. 2007

J Pharmacol Exp Ther

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To enhance our understanding of the physiological roles of heme oxygenase (HO) isozymes, HO-1 (inducible) and HO-2 (constitutive), we developed novel imidazole-based HO inhibitors. Unlike the metalloporphyrins, these imidazole-dioxolane compounds are selective for the in vitro inhibition of HO with minimal effects on other heme-dependent enzymes such as nitric oxide synthase and soluble guanylyl cyclase. In the current study, we tested the hypothesis that these novel HO inhibitors are effective in intact cells by extending their application to cultured, renal proximal tubule epithelial cells (LLC-PK 1 ). HO-1 and HO-2 protein expression was enhanced by pretreatment of cells with hemin, transduction with adenovirus encoding human HO-1, and transfection with cDNA for HO-2, respectively. Total HO activity was measured by determining the formation of carbon monoxide (CO), whereas cell viability and apoptosis were measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the expression of activated caspase-3. Gliotoxin/tumor necrosis factor-␣ (TNF-␣) produced cytotoxicity in wild-type LLC-PK 1 cells (P Ͻ 0.05) but not in HO-1 and HO-2 overexpressing or wild type cells pretreated with hemin (10 M). The presence of imidazole-dioxolane HO inhibitors (2-25 M) decreased cell viability (P Ͻ 0.05). A CO-releasing molecule reversed, in a dose-dependent manner, the cytotoxic effects and caspase-3 activation induced by the combination of gliotoxin/TNF-␣ and the HO inhibitors, suggesting an important role for CO in protection against renal toxicity. These data demonstrate a protective role of both HO-1 and HO-2 against gliotoxin/TNF-␣-induced cytotoxicity in LLC-PK 1 cells. The novel imidazole-dioxolane compounds can be used as effective inhibitors of HO activity in cell culture.

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Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule

Cited by 115 publications

References 33 publications

HIF Activation Protects From Acute Kidney Injury

HIF Activation Protects From Acute Kidney Injury

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

Effectiveness of Novel Imidazole-Dioxolane Heme Oxygenase Inhibitors in Renal Proximal Tubule Epithelial Cells

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