Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage

Francescato, Heloı́sa Della Coletta; Costa, R. S.; Silva, Cleonice G. A. da; Coimbra, Terezila Machado

doi:10.1016/j.lfs.2009.02.004

Cited by 40 publications

(30 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Other studies further identified MAPK as key upstream regulators for the activation of TNF-α and caspase-3 in response to oxidative stress. [5][6][7][8][9] In light of these results, it is noteworthy that ECG decreased ROS activity and prevented downstream activation of MAPK/inflammation and apoptosis.…”

Section: Discussionmentioning

confidence: 83%

“…Various studies have shown that pharmacological modulation of these proteins can attenuate the toxic effects of cisplatin in kidney. [5][6][7][8][9] Recent studies have revealed that green tea has healthprotecting benefits, especially in the prevention of diseases associated with free radicals and reactive oxygen species (ROS), such as cancer, cardiovascular, and neurodegenerative diseases. [10][11][12] These beneficial effects are attributed to green tea catechins such as epicatechin gallate (ECG) and may be due to the presence gallate in the 3′ position.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular mechanisms underlying attenuation of cisplatin-induced acute kidney injury by epicatechin gallate

Malik

Suchal

Bhatia

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

Cisplatin, a platinum compound, is used as a first-line agent against various forms of solid cancers. Nephrotoxicity is an important adverse effect of cisplatin therapy, which involves increased oxidative stress, inflammation, apoptosis, and activation of the mitogen-activated protein kinase (MAPK) pathway. It is well known that the bioactive compounds present in green tea are used to treat various disorders due to their biological activities. With this background, the present study was aimed to investigate the effect of epicatechin gallate (ECG), a green tea polyphenol, in cisplatin-induced nephrotoxicity in rats. To achieve this, ECG (1.25, 2.5, and 5 mg/kg; intraperitoneal (i.p.)) was administered to male albino Wistar rats for the period of 10 days. On the 7th day, a single i.p. injection of cisplatin (8 mg/kg) was injected into rats to produce kidney injury and the animals were then killed on the 10th day. Cisplatin toxicity was associated with enhanced oxidative stress, impaired renal function along with marked tubular necrosis in Histopathology. Furthermore, cisplatin activated the MAPK pathway, which contributed to inflammation and apoptosis in the kidney of treated rats. In contrast, ECG (5 mg/kg) pretreatment normalized cisplatin-induced oxidative stress, renal function, and histopathological changes. ECG also prevented the activation of the MAPK pathway, and attenuated inflammation and apoptosis in rats. These findings suggest that ECG prevented cisplatin-induced oxidative stress, inflammation, and apoptosis by downregulating the MAPK pathway and resulted in improved renal function.

show abstract

Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 99%

Molecular mechanisms underlying attenuation of cisplatin-induced acute kidney injury by epicatechin gallate

Malik

Suchal

Bhatia

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…In addition to being a major intermediary in the response to cDDP, p38 MAPK is also implicated in some of the side effects provoked by cDDP such as nephrotoxicity [46]. Consequently, evaluation of the status of this signaling pathway is of interest for determining the likelihood of both chemoresistance and cDDP-associated side-effects.…”

Section: Discussionmentioning

confidence: 99%

Balance between MKK6 and MKK3 Mediates p38 MAPK Associated Resistance to Cisplatin in NSCLC

Moya¹,

Cruz-Morcillo²,

Valero³

et al. 2011

PLoS ONE

View full text Add to dashboard Cite

The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin.

show abstract

“…In contrast, inhibitors of MAPK significantly ameliorated IS-induced apoptosis of NRK-52E cells. Francescato et al 32 reported that the blockade of p38 MAPK activation is associated with reduction of the inflammatory process, oxidative stress, and apoptotic cell death in cisplatin-induced renal damage. Ciglitazoneinduced cell death was also reduced by transfection of smallinterfering RNA of p38 MAPK, indicating involvement of p38 MAPK in ciglitazone-induced cell death.…”

Section: Is-induced Emt and Apoptosis Sh Kim Et Almentioning

confidence: 99%

Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease

Kim

Ryu

et al. 2012

Laboratory Investigation

View full text Add to dashboard Cite

Indoxyl sulfate (IS), one of the uremic toxins, is regarded to have a substantial role in the progression of chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) and apoptosis of renal tubular cells are known to be the critical mechanisms of the development and aggravation of CKD. We investigated the effect of IS on EMT and apoptosis in renal proximal tubular cells, NRK-52E cells. IS significantly inhibited cell proliferation and induced cell migration with a morphological transition from cuboidal epithelial cells to spindle-shaped scattered fibroblast-like cells. IS downregulated the expressions of zonula occluden-1 and E-cadherin, whereas upregulated a-SMA expression at 48 h, which was blocked by a pretreatment of the organic anion transporter, probenecid. IS also induced apoptosis of NRK cells from a concentration of 25 mg/ml with an activation of ERK1/2 and p38 MAP kinase (MAPK). Pretreatment of ERK1/2 or p38 MAPK inhibitors, PD98059 or SB203580, resulted in no significant effect on IS-induced EMT, whereas it ameliorated IS-induced apoptosis of NRK cells. These findings suggested phenotypic transition and apoptosis as potential mechanisms of IS-induced renal damage and the differential role of MAPK activation in IS-induced EMT and apoptosis of renal tubular cells. KEYWORDS: apoptosis; chronic kidney disease; epithelial-to-mesenchymal transition; indoxyl sulfate; MAPKinase Indoxyl sulfate (IS) is one of the protein-bound uremic solutes derived from tryptophan, which is converted to indole and subsequently undergoes sulfate conjugation in hepatocytes to form IS.1 It is taken by organic anion transporters (OATs) at the basolateral membrane of proximal tubular cells, and excreted mostly into urine through tubular secretion.2 Therefore, IS accumulates in patients with chronic kidney disease (CKD), 3 demonstrated as an increase in serum level and positive immunostaining area of IS in the kidneys. 4 Although IS is regarded as a marker of renal dysfunction, recent data have revealed that IS also has a substantial role in the progression of CKD.5 Indole, the precursor of IS, caused glomerular sclerosis in uremic rats, 6 and oral administration of IS increased serum creatinine and decreased inulin clearance in uremic rats.3 In a clinical study, patients with urinary IS levels 490 mg/day showed faster progression rate of CKD than did those with urinary IS o30 mg/day.7 Furthermore, the administration of oral adsorbent of IS resulted in a decrease in glomerular sclerosis and interstitial fibrosis in uremic rats associated with a decrease in plasma and urinary IS levels.3 Lowering IS also resulted in an improvement of renal function and a delay in the initiation of dialysis in CKD patients. 8 In a multicenter, randomized clinical study, Schulman et al 9 showed that an administration of AST-120, oral adsorbent of IS, ameliorated uremic symptoms in a dose-dependent manner with a decrease in serum IS and a stable maintenance of serum creatinine. The mechanism of IS-induced renal progression has been expla...

show abstract

Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage

Cited by 40 publications

References 45 publications

Molecular mechanisms underlying attenuation of cisplatin-induced acute kidney injury by epicatechin gallate

Molecular mechanisms underlying attenuation of cisplatin-induced acute kidney injury by epicatechin gallate

Balance between MKK6 and MKK3 Mediates p38 MAPK Associated Resistance to Cisplatin in NSCLC

Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease

Contact Info

Product

Resources

About