Mai M. Helmy

Abstracts

3 Lack of Functional Interaction between Nitric Oxide and ET-A Receptors in Cisplatin-Induced Acute Renal Failure

Authors: Mai M. Helmy

Abstract:

Although the role of either nitric oxide (NO) or endothelin receptors modulation in the severity of cisplatin-induced nephrotoxicity has been recognized in previous studies including our own, the possible interaction between the two pathways remains obscure. In this study, we tested the possible interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats. Sprague Dawley male rats (200 to 250 g) were divided into four groups: Control (given a single dose of normal saline, i.p.), cisplatin (6 mg/kg, i.p.), cisplatin+Sildenafil (2 mg/kg, i.p.), cisplatin+Sildenafil+BQ-123 (1 mg/kg, i.p.). Each of the co-administered drugs was given in two doses; one hour before and one day after the cisplatin dose. Acute cisplatin administration resulted in significant increases in BUN and serum creatinine levels at 96 h following cisplatin injection. Increased levels of MDA, TNF-α and caspase-3, decreased nitrite/nitrate level and SOD activity in kidney homogenates were also observed following cisplatin injection. According to the obtained results, the co-adminstration of sildenafil alone with cisplatin offered a reno-protective effect comparable to that obtained following the concurrent administration of both sildenafil and the selective ETAR antagonist BQ-123. Thus, the current study is the first to reveal that the presence of an intact NO/cGMP system may offer a moderate reno-protective effect against cisplatin-induced nephrotoxicity even in the presence of ETAR-mediated vasoconstriction, suggesting the absence of obvious functional interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats.

Keywords: nephrotoxicity, BQ-123, cisplatin, endothelin-1, sildenafil

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2 Pioglitazone Ameliorates Methotrexate-Induced Renal Endothelial Dysfunction via Amending Detrimental Changes in Antioxidant Profile, Systemic Cytokines and Fas Production

Authors: Sahar M. El-Gowilly, Mai M. Helmy, Hanan M. El-Gowelli

Abstract:

Methotrexate (MTX) is widely used in treatment of cancers and autoimmune diseases. However, nephrotoxicity is one of its most important side effects. The peroxisome proliferator-activated receptor gamma agonist, pioglitazone, is known to exert antiinflammatory and reno-protective effects in various kidney injuries. The purpose of this study was to investigate the potential involvement of endothelial damage in MTX-induced renal injury and to elaborate the possible protective effect of pioglitazone against MTX-induced endothelial impairment. Compared with saline-treated rats, treatment with MTX (7 mg/kg for 3 day) caused significant elevations in serum levels of urea and creatinine, increased renal nitrate/nitrite level and impaired renovascular responsiveness of isolated perfused kidney to endothelium-dependent vasodilations induced by acetylcholine (0.01-2.43 nmol) and isoprenaline (1µmol). These effects were abolished by concurrent treatment with pioglitazone (2.5 mg/kg, for 5 days starting two days before MTX). Alternatively, MTX treatment did not affect endothelium-independent renovascular relaxation induced by sodium nitroprusside (0.001-10 μmole). The possibility that alterations in renal antioxidants, circulating cytokine and apoptotic factor (Fas) levels contributed to MTX-pioglitazone interaction was assessed. Pioglitazone treatment abrogated renal oxidative stress (decreased reduced glutathione and catalase activity and increased malondialdehyde), elevated serum cytokine (interleukin-6, interleukin-10, tumor necrosis factor-alpha and transforming growth factor-beta1) and Fas induced by MTX. Histologically, MTX caused defused tubular cells swelling and vacuolization associated with endothelial damage in renal arterioles. These effects disappeared upon co-treated with pioglitazone. Collectively, pioglitazone abolished MTX-induced endothelium dysfunction and nephrotoxicity via ameliorating oxidative stress and rectifying cytokines and Fas abnormalities caused by MTX.

Keywords: Kidney, methotrexate, pioglitazone, endothelium

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1 Pioglitazone Ameliorates Methotrexate-Induced Renal Endothelial Dysfunction via Amending Detrimental Changes in Antioxidant Profile, Systemic Cytokines and Apoptotic Factors

Authors: Sahar M. El-Gowilly, Mai M. Helmy, Hanan M. El-Gowelli

Abstract:

Methotrexate (MTX) is widely used in treatment of cancers and autoimmune diseases. However, nephrotoxicity is one of the most important side effects of MTX. The peroxisome proliferator-activated receptor gamma agonist, pioglitazone (PIO), is known to exert anti-inflammatory and reno-protective effects in various kidney injuries. The purpose of this study was to investigate the potential involvement of endothelial damage in MTX-induced renal injury and to elaborate the possible protective effect of PIO against MTX-induced nephropathy. Compared with saline-treated rats, treatment with MTX (7 mg/kg for 3 day) caused significant elevations in serum levels of urea and creatinine, increased renal nitrate/nitrite level and impaired renovascular responsiveness of isolated perfused kidney to endothelium-dependent vasodilations induced by acetylcholine (0.01-2.43 nmol) and isoprenaline (1µmol). These effects were abolished by concurrent treatment with PIO (2.5 mg/kg, for 5 days starting two days before MTX). Alternatively, MTX treatment did not affect endothelium-independent renovascular relaxation induced by sodium nitroprusside (1-30 μmole). The possibility that alterations in renal antioxidants, circulating cytokine and apoptotic factor (Fas) levels contributed to MTX-PIO interaction was assessed. PIO treatment abrogated renal oxidative stress (decreased reduced glutathione and catalase activity and increased malondialdehyde), elevated serum cytokine (interleukin-6, interleukin-10, tumor necrosis factor-alpha and transforming growth factor-beta1) and Fas induced by MTX. Histologically, MTX caused defused tubular cells swelling and vacuolization associated with endothelial damage in renal arterioles. These effects disappeared upon co-treated with PIO. Collectively, PIO abolished MTX-induced endothelium dysfunction and nephrotoxicity via ameliorating oxidative stress and rectifying cytokines and Fas abnormalities caused by MTX.

Keywords: Kidney, methotrexate, pioglitazone, endothelium

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