Cisplatin-induced kidney injury in the rat: l-carnitine modulates the relationship between MMP-9 and TIMP-3

Martinez, G; Costantino, Giuseppe; Clementi, Anna; Puglia, Michele; Clementi, Silvia; Cantarella, Giuseppina; Meo, L. De; Matera, M

doi:10.1016/j.etp.2008.07.004

Cited by 15 publications

(9 citation statements)

References 14 publications

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“…It is well known that cisplatin administered to rats damages the proximal tubule [2,4,14,16,19,21] and that the kidney injury induced by cisplatin is similar to ischemic damage [6,29]. The acute renal failure caused by cisplatin is typically characterized by signs such as a severe reduction in the glomerular filtration rate (GFR) [24], a variable fall in the renal blood flow [6,29], a decrease in urinary concentrating ability and changes in urine volume and creatinine clearance [20].…”

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confidence: 99%

Protective Effect of Lactoferrin on Cisplatin-Induced Nephrotoxicity in Rats

Kimoto

Nishinohara

Sugiyama

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Although cisplatin (cis-diamminedichloroplatinum II) is one of the most effective chemotherapeutic agents, its clinical use is limited because of its strong side effects on the kidneys. The aim of this study was to investigate the renoprotective effect of bovine lactoferrin (bLf) in cisplatin-induced renal failure in rats. To assess the renoprotective effect of bLf, oral bLf (300 mg/kg) was administered from the day before to the fifth day after cisplatin (7 mg/kg, i.p.) injection. Daily administration of bLf histologically reduced renal tubular injury induced by cisplatin and suppressed the deterioration of renal function. Accumulated platinum content in the kidney was significantly decreased by the daily administration of bLf. Moreover, the administration of intravenous bLf caused a significant increase in urine volume in a dose-dependent manner. These results suggest that pretreatment with bLf produces a protective effect against cisplatininduced nephrotoxicity. This protective effect of bLf involves the reduction of accumulated cisplatin in the kidney.

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confidence: 99%

Protective Effect of Lactoferrin on Cisplatin-Induced Nephrotoxicity in Rats

Kimoto

Nishinohara

Sugiyama

et al. 2013

The Journal of Veterinary Medical Science

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“…Among those, the activation and expression of MMPs, a common mechanism of BBB leakiness, was often referred after METH exposure [4,6,9]. Based on previous reports where L-carnitine was seen to decrease glomerular sclerosis and interstitial fibrosis after cisplatin treatment, by reducing MMP-9 activity [46], and ALC administration was shown to ameliorate MMP-related dystrophy [47], we hypothesized that ALC could prevent METH-induced MMPs activity contributing this way to maintain the integrity of the endothelial monolayer. Increased MMP-9 activity after METH exposure was previously reported in brain regions associated to the reward system [6,9].…”

Section: Discussionmentioning

confidence: 99%

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

et al. 2014

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Methamphetamine (METH) is a potent psychostimulant highly used worldwide. Recent studies evidenced the involvement of METH in the breakdown of the blood-brain-barrier (BBB) integrity leading to compromised function. The involvement of the matrix metalloproteinases (MMPs) in the degradation of the neurovascular matrix components and tight junctions (TJs) is one of the most recent findings in METH-induced toxicity. As BBB dysfunction is a pathological feature of many neurological conditions, unveiling new protective agents in this field is of major relevance. Acetyl-L-carnitine (ALC) has been described to protect the BBB function in different paradigms, but the mechanisms underling its action remain mostly unknown. Here, the immortalized bEnd.3 cell line was used to evaluate the neuroprotective features of ALC in METH-induced damage. Cells were exposed to ranging concentrations of METH, and the protective effect of ALC 1 mM was assessed 24 h after treatment. F-actin rearrangement, TJ expression and distribution, and MMPs activity were evaluated. Integrin-linked kinase (ILK) knockdown cells were used to assess role of ALC in ILK mediated METHtriggered MMPs' activity. Our results show that METH led to disruption of the actin filaments concomitant with claudin-5 translocation to the cytoplasm. These events were mediated by MMP-9 activation in association with ILK overexpression. Pretreatment with ALC prevented METH-induced activation of MMP-9, preserving claudin-5 location and the structural arrangement of the actin filaments. The present results support the potential of ALC in preserving BBB integrity, highlighting ILK as a new target for the ALC therapeutic use.

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“…It has been reported that the pathophysiological mechanisms leading to renal interstitial fibrosis are considered to be related not directly to the primary effect of CDDP, but to the activation of pro-inflammatory and pro-fibrotic factors 22) and imbalance between extracellular matrix synthesis and degradation. 16) Although the detail mechanism of chronic nephrotoxicity remains uncertain, there is a lot of information about the mechanism of AKI as described in the introduction. Therefore, sCKI and AKI may be caused by different pathways.…”

Section: Discussionmentioning

confidence: 99%

“…15) sCKI induced by repeated CDDP administration is often associated with renal interstitial fibrosis and may be irreversible, potentially leading to chronic kidney disease. 16,17) Therefore, the management of not only AKI but also sCKI induced by CDDP in multiple cycles plays an important role in the outcome of CDDP-based chemotherapy. However, little information is available on the relationship between PK and nephrotoxicity of CDDP under repeated administration.…”

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confidence: 99%

Alterations in Cisplatin Pharmacokinetics and Its Acute/Sub-chronic Kidney Injury over Multiple Cycles of Cisplatin Treatment in Rats

Okada

Fukushima

Fujita

et al. 2017

Biological & Pharmaceutical Bulletin

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Cisplatin (CDDP)-induced acute kidney injury (AKI) is a major clinical concern. CDDP treatment is generally conducted with multiple cycles; the magnitude of the CDDP-induced AKI may be altered by these cycles. Moreover, sub-chronic kidney injury (sCKI) induced by repeated CDDP treatment is often associated with renal interstitial fibrosis, potentially leading to chronic kidney disease. Therefore, it is suggested that the management of not only AKI but also sCKI induced by CDDP in multiple cycles plays an important role in the outcome of CDDP-based chemotherapy. This study investigated the alteration in pharmacokinetics and toxicodynamics of CDDP that was repeatedly administered for three cycles in rats; a cycle consisted of CDDP (5.0 mg/kg, bolus injection) followed by a 21-d washout period. AKI and sCKI were evaluated by plasma creatinine concentration. In repeated multiple administration of CDDP, renal clearance was decreased and the amounts of accumulated Pt in kidneys increased by the cycle. AKI and sCKI were similarly exacerbated by the cycle, whereas the degree of AKI showed a large inter-and intra-individual variation in each cycle. However, the degree of sCKI constantly increased (creatinine increasing ratio in any cycle is about 150%), suggesting that the degree of sCKI in any given cycle was predictable by monitoring the initial creatinine baseline. In this study, therefore, it is suggested that the evaluation of sCKI by monitoring creatinine concentration at base is important for the estimation of CDDP-induced nephrotoxicity. These results may provide useful information for more effective and safe CDDP-based chemotherapy with evidence-based dose adjustment.Key words cisplatin; repeated administration; pharmacokinetics; creatinine; kidney injury Cisplatin [cis-diamminedichloroplatinum (II), CDDP] is widely used as a key antitumor agent. However, despite its clinical usefulness, CDDP-induced nephrotoxicity is one of the dose-limiting side effects and a major clinical concern; recent retrospective studies have reported that approximately one-third of patients treated with CDDP-based chemotherapy experience acute kidney injury (AKI), even with plausible renoprotective strategies such as co-administration with hydration.1,2) Therefore, the prediction and prevention of CDDPinduced AKI still remain a challenge.The pharmacokinetics (PK) of CDDP and the pathophysiology of CDDP-induced AKI have been intensively investigated. A unique feature of CDDP PK is the non-specific and irreversible binding of CDDP to proteins; after administration, CDDP rapidly and irreversibly binds to plasma proteins to form inactive CDDP complexes.3,4) Therefore, irreversible binding of CDDP to plasma proteins should be considered as metabolic inactivation. Unbound CDDP is excreted mainly by glomerular filtration and partially by active transport mediated via organic cation transporter (OCT)-2 and multi-drug and toxin extrusion transporter 2.5,6) During distribution and excretion processes, CDDP accumulates in proximal tubular epithel...

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Cisplatin-induced kidney injury in the rat: l-carnitine modulates the relationship between MMP-9 and TIMP-3

Cited by 15 publications

References 14 publications

Protective Effect of Lactoferrin on Cisplatin-Induced Nephrotoxicity in Rats

Protective Effect of Lactoferrin on Cisplatin-Induced Nephrotoxicity in Rats

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

Alterations in Cisplatin Pharmacokinetics and Its Acute/Sub-chronic Kidney Injury over Multiple Cycles of Cisplatin Treatment in Rats

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