Protective effect of proanthocyanidins against doxorubicin‐induced nephrotoxicity in rats

El-Sayed, El-Sayed M.; Mansour, Ahmed M.; El-Sawy, Waleed S.

doi:10.1002/jbt.21965

Cited by 48 publications

(23 citation statements)

References 50 publications

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“…A huge number of studies demonstrated that oxidative stress has an important role in CsA‐induced nephrotoxicity . Also, as shown in many reports, antioxidant therapy appears to alleviate nephrotoxicity . In a previous study of ours, it was shown that CsA‐treated rats had higher serum soluble Klotho (a protein with antiaging and antioxidant properties) and oxidative stress markers than those in controls.…”

Section: Discussionsupporting

confidence: 66%

Oxidative stress‐induced renal telomere shortening as a mechanism of cyclosporine‐induced nephrotoxicity

Raeisi

Ghorbanihaghjo

Argani

et al. 2018

J Biochem & Molecular Tox

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Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine-A exerts its nephrotoxic side effects via induction of oxidative stress-induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8-hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine-A treatment significantly (P < 0.05) enhanced renal malondialdehyde, 8-hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine-A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine-induced oxidative stress, indicating the potential mechanism of cyclosporine-induced nephrotoxicity.

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Section: Discussionsupporting

confidence: 66%

Oxidative stress‐induced renal telomere shortening as a mechanism of cyclosporine‐induced nephrotoxicity

Raeisi

Ghorbanihaghjo

Argani

et al. 2018

J Biochem & Molecular Tox

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“…Alterations in the RAS have been shown to contribute to the development of AKI and are associated with adverse outcomes both in experimental and clinical studies [45][46][47][48][49][50]. Several components of the kidney RAS, such as urine Angiotensinogen and Ang II, the main active peptide, are increased in experimental AKI caused by ischemia-reperfusion AKI [45][46][47][51][52][53][54][55][56] ACE inhibitors (ACEi) and angiotensin receptor antagonists (ARBs) may attenuate renal inflammation, injury and improve renal function in the ischemia-reperfusion model of AKI [57][58][59][60]. Intrarenal Ang II is reportedly elevated in AKI, which may worsen kidney tissue injury independently of its hemodynamic effect that helps maintain renal circulation [61][62][63].…”

Section: Discussionmentioning

confidence: 99%

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

2019

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ACE2 is a monocarboxypeptidase which generates Angiotensin (1-7) from Angiotensin II (1-8). Attempts to target the kidney Renin Angiotensin System using native ACE2 to treat kidney disease are hampered by its large molecular size, 100 kDa, which precludes its glomerular filtration and subsequent tubular uptake. Here, we show that both urine and kidney lysates are capable of digesting native ACE2 into shorter proteins of~60-75 kDa and then demonstrate that they are enzymatically very active. We then truncated the native ACE2 by design from the C-terminus to generate two short recombinant (r)ACE2 variants (1-605 and 1-619AA). These two truncates have a molecular size of~70 kDa, as expected from the amino acid sequence and as shown by Western blot. ACE2 enzyme activity, measured using a specific substrate, was higher than that of the native rACE2 (1-740 AA). When infused to mice with genetic ACE2 deficiency, a single i.v. injection of 1-619 resulted in detectable ACE2 activity in urine, whereas infusion of the native ACE2 did not. Moreover, ACE2 activity was recovered in harvested kidneys from ACE2-deficient mice infused with 1-619, but not in controls (23.1 ± 4.3 RFU/µg creatinine/h and 1.96 ± 0.73 RFU/µg protein/hr, respectively). In addition, the kidneys of ACE2-null mice infused with 1-619 studied ex vivo formed more Ang (1-7) from exogenous Ang II than those infused with vehicle (AUC 8555 ± 1933 vs. 3439 ± 753 ng/mL, respectively, p < 0.05) further demonstrating the functional effect of increasing kidney ACE2 activity after the infusion of our short ACE2 1-619 variant. We conclude that our novel short recombinant ACE2 variants undergo glomerular filtration, which is associated with kidney uptake of enzymatically active proteins that can enhance the formation of Ang (1-7) from Ang II. These small ACE2 variants may offer a potentially useful approach to target kidney RAS overactivity to combat kidney injury.

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“…Although the exact mechanism of DOX-induced hepatotoxicity and nephrotoxicity remains unknown, it is believed that the toxic effects are mediated by free radical formation, iron-dependent oxidative damage of biological macromolecules, membrane lipid peroxidation, and protein oxidation [15,19,24,25,26,66,67]. Moreover, nitric oxide synthase may be responsible for the reductive activation of DOX to its free radical semiquinone form, and the subsequent oxygen radical-mediated cellular damage.…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of Amifostine against Multiple-Dose Doxorubicin-Induced Toxicity in Rats

Jaćević

Dragojević-Simić

Tatomirovic

et al. 2018

IJMS

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Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals’ whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales—hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.

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Protective effect of proanthocyanidins against doxorubicin‐induced nephrotoxicity in rats

Cited by 48 publications

References 50 publications

Oxidative stress‐induced renal telomere shortening as a mechanism of cyclosporine‐induced nephrotoxicity

Oxidative stress‐induced renal telomere shortening as a mechanism of cyclosporine‐induced nephrotoxicity

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

The Efficacy of Amifostine against Multiple-Dose Doxorubicin-Induced Toxicity in Rats

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