Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways

Objectives: Geraniol, a natural monoterpene, is an essential oil component of many plants. Methotrexate is an anti-metabolite drug, used for cancer and autoimmune conditions; however, clinical uses of methotrexate are limited by its concomitant renal injury. This study investigated the efficacy of geraniol to prevent methotrexate-induced acute kidney injury and via scrutinizing the Keap1/Nrf2/HO-1, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 and -9 pathways. Methods: Male Wister rats were allocated into five groups: control, geraniol (orally), methotrexate (IP), methotrexate and geraniol (100 and 200 mg/kg). Results: Geraniol effectively reduced the serum levels of creatinine, urea and Kim-1 with an increase in the serum level of albumin when compared to the methotrexate-treated group. Geraniol reduced Keap1, escalated Nrf2 and HO-1, enhanced the antioxidant parameters GSH, SOD, CAT and GSHPx and reduced MDA and NO. Geraniol decreased renal P38 MAPK and NF-κB and ameliorated the inflammatory mediators TNF-α, IL-1β, IL-6 and IL-10. Geraniol negatively regulated the apoptotic mediators Bax and caspase-3 and -9 and increased Bcl2. All the biochemical findings were supported by the alleviation of histopathological changes in kidney tissues. Conclusion: The current findings support that co-administration of geraniol with methotrexate may attenuate methotrexate-induced acute kidney injury.

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Effect of Thymoquinone on Acute Kidney Injury Induced by Sepsis in BALB/c Mice

BioMed Research International ◽

10.1155/2020/1594726 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Li-Peng Guo ◽

Si-Xu Liu ◽

Qin Yang ◽

Hong-Yang Liu ◽

Lu-Lu Xu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Caspase 3 ◽

Nigella Sativa ◽

Cecal Ligation ◽

Kidney Tissue ◽

Kidney Injury ◽

Serum Levels ◽

Caspase 8 ◽

Protective Effects ◽

Caspase 1

Acute kidney injury (AKI) is a common complication of sepsis and has also been observed in some patients suffering from the new coronavirus pneumonia COVID-19, which is currently a major global concern. Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds. It has a variety of beneficial properties including anti-inflammatory and antioxidative activities. Here, we investigated the possible protective effects of TQ against kidney damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ+CLP. CLP was performed after 2 weeks of TQ gavage. After 48 h, we measured the histopathological alterations in the kidney tissue and the serum levels of creatinine (CRE) and blood urea nitrogen (BUN). We also evaluated pyroptosis (NLRP3, caspase-1), apoptosis (caspase-3, caspase-8), proinflammatory (TNF-α, IL-1β, and IL-6)-related protein and gene expression levels. Our results demonstrated that TQ inhibited CLP-induced increased serum CRE and BUN levels. It also significantly inhibited the high levels of NLRP3, caspase-1, caspase-3, caspase-8, TNF-α, IL-1β, and IL-6 induced by CLP. Furthermore, NF-κB protein level was significantly decreased in the TQ+CLP group than in the CLP group. Together, our results indicate that TQ may be a potential therapeutic agent for sepsis-induced AKI.

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Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis

BioMed Research International ◽

10.1155/2021/6636621 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Mei Yang ◽

Jin-tao Fang ◽

Ni-shang Zhang ◽

Long-jiang Qin ◽

Yang-yang Zhuang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cecal Ligation ◽

Kidney Tissue ◽

Kidney Injury ◽

Serum Levels ◽

Interleukin 18 ◽

Tissue Samples ◽

Caspase 1 ◽

Tnf Α ◽

Histologic Changes

Objective. To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily. Methods. Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) ( n = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1β (IL-1β), interleukin-18 (IL-18), TNF-α, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1β, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues. Results. AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level ( P < 0.05 ). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1β, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls ( P < 0.05 ). Conclusions. We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.

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Reno-protective effect of exogenous glutathione on experimentally-induced acute kidney injury in male rats.

10.21203/rs.3.rs-118623/v1 ◽

2020 ◽

Author(s):

Yahya Naguib ◽

Eman Elgizawy

Keyword(s):

Acute Kidney Injury ◽

Renal Failure ◽

Cystatin C ◽

Kidney Injury ◽

Serum Levels ◽

Treated Group ◽

Male Rats ◽

Control Group ◽

Distilled Water ◽

Mrna Levels

Abstract Background: Acute kidney injury (AKI) or Acute renal failure (ARF) refers to the sudden damage or failure of the kidney within few hours or days and resulting in acute deterioration of the renal functions. If not properly treated, AKI may lead to chronic renal failure and possibly renal transplantation. The aim of the present study was to evaluate the role of exogenous glutathione (GSH) on ciprofloxacin (GFX)-induced AKI. We also studied the effect of glutathione administration on some genes of interest.Methods: Forty male Wistar albino rats were equally divided into 4 groups. The control group received intra-peritoneal injection of distilled water for 15 consequent days. The GSH treated group received concomitant intra-peritoneal injection of distilled water and glutathione (200 mg/kg/day) for 15 consequent days. The CFX treated group received concomitant intra-peritoneal injection of distilled water and ciprofloxacin (800 mg/kg/day) for 15 consequent days. The CFX+GSH treated group received concomitant intra-peritoneal injection of CFX and CSH for 15 consequent days. Serum levels of creatinine, urea, cystatin C and GGT were measured. Renal CYP4F1, GPx, GSR gene expression was evaluated.Results: Exogenous GSH had no significant effect on the kidney functions or the studied genes when compared to the control group. Treatment with CFX resulted in significant increase (P<0.05) in creatinine, urea, cystatin C and GGT serum levels when compared to the control group. CFX treatment also significantly (P<0.05) down-regulated renal GPx, GSR mRNA levels, while it up-regulated renal CYP4F1, when compared to the corresponding values in the control rats. Serum levels of urea, creatinine and cystatin C were significantly lower (P<0.05) in CFX+GSH group when compared to the CFX treated rats. There was significant up-regulation (P<0.05) of the renal, GPx, GSR and down-regulation of CYP4F1 mRNA levels in the CFX+GSH group when compared to the corresponding values in the CFX treated group.Conclusion: Our results suggest a potential prophylactic and possibly therapeutic roles of exogenous GSH administration in the treatment of drug-induced AKI. We also demonstrated that the underlying mechanism could be explained, at least in part, by the antioxidant and gene modifying properties of GSH.

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Hepatic ischemia reperfusion injury: effect of moderate intensity exercise and oxytocin compared to l-arginine in a rat model

Egyptian Liver Journal ◽

10.1186/s43066-021-00111-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amr H. ELKady ◽

Bataa M. Elkafoury ◽

Dalia A. Saad ◽

Doaa M. Abd el-Wahed ◽

Walaa Baher ◽

...

Keyword(s):

Ischemia Reperfusion ◽

Serum Levels ◽

Treated Group ◽

Significant Decline ◽

Moderate Intensity ◽

Trained Group ◽

Moderate Intensity Exercise ◽

Hepatic Ischemia ◽

Tnf Α ◽

Hepatic Ischemia Reperfusion

Abstract Background Hepatic ischemia reperfusion (IR) injury is considered as a main cause of liver damage and dysfunction. The l-arginine/nitric oxide pathway seems to be relevant during this process of IR. Although acute intense exercise challenges the liver with increased reactive oxygen species (ROS), regular training improves hepatic antioxidant status. Also, oxytocin (Oxy), besides its classical functions, it exhibits a potent antistress, anti-inflammatory, and antioxidant effects. This study was designed to evaluate the hepatic functional and structural changes induced by hepatic IR injury in rats and to probe the effect and potential mechanism of moderate intensity exercise training and/or Oxy, in comparison to a nitric oxide donor, l-arginine, against liver IR-induced damage. Results Compared to the sham-operated control group, the hepatic IR group displayed a significant increase in serum levels of ALT and AST, plasma levels of MDA and TNF-α, and significant decrease in plasma TAC and nitrite levels together with the worsening of liver histological picture. L-Arg, Oxy, moderate intensity exercise, and the combination of both Oxy and moderate intensity exercises ameliorated these deleterious effects that were evident by the significant decrease in serum levels of ALT and AST, significant elevation in TAC and nitrite, and significant decline in lipid peroxidation (MDA) and TNF-α, besides regression of histopathological score regarding hepatocyte necrosis, vacuolization, and nuclear pyknosis. Both the moderate intensity exercise-trained group and Oxy-treated group showed a significant decline in TNF-α and nitrite levels as compared to l-Arg-treated group. The Oxy-treated group showed statistical insignificant changes in serum levels of ALT, AST, and plasma levels of nitrite, MDA, TAC, and TNF-α as compared to moderate intensity exercise-trained group. Conclusion The combination of both moderate intensity exercise and Oxy displayed more pronounced hepatoprotection on comparison with l-Arg which could be attributed to their more prominent antioxidant and anti-inflammatory effects but not due to their NO-enhancing effect.

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Clearance of inflammatory cytokines in patients with septic acute kidney injury during renal replacement therapy using the EMiC2 filter (Clic-AKI study)

Critical Care ◽

10.1186/s13054-021-03476-x ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Nuttha Lumlertgul ◽

Anna Hall ◽

Luigi Camporota ◽

Siobhan Crichton ◽

Marlies Ostermann

Keyword(s):

Acute Kidney Injury ◽

Growth Factor ◽

Replacement Therapy ◽

Kidney Injury ◽

Final Analysis ◽

Adsorptive Capacity ◽

Clearance Rates ◽

Plasma Cytokine ◽

Tnf Α ◽

Ifn Γ

Abstract Background The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. Methods This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. Results Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1β, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. Conclusion EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. Trial registration: NCT03231748, registered on 27th July 2017.

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α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

AJP Renal Physiology ◽

10.1152/ajprenal.00143.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. F1443-F1453 ◽

Cited By ~ 46

Author(s):

Chung-Hsi Hsing ◽

Chiou-Feng Lin ◽

Edmund So ◽

Ding-Ping Sun ◽

Tai-Chi Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Histone Deacetylases ◽

Trichostatin A ◽

Histone H3 ◽

Cecal Ligation ◽

Kidney Injury ◽

Protective Effects ◽

Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

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P–061 Protective effect of melatonin against bleomycin, etoposide, and cisplatin (BEP) chemotherapy-induced testicular toxicity in Wistar rats: A biochemical, immunohistochemical and apoptotic genes based evidence

Human Reproduction ◽

10.1093/humrep/deab130.060 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

M Moradi ◽

A Faramarzi ◽

N Goodarzi ◽

A H Hashemian ◽

H Cheraghi ◽

...

Keyword(s):

Testosterone Level ◽

Wistar Rats ◽

Caspase 3 ◽

Treated Group ◽

Serum Testosterone Level ◽

Dependent Manner ◽

Qrt Pcr ◽

Tnf Α ◽

Significant Difference ◽

Bep Chemotherapy

Abstract Study question Does exogenous melatonin (MLT) attenuate BEP-induced damage in testicular cells and spermatogenesis in a dose-dependent manner? Summary answer Melatonin protected the testes against BEP-induced testis damage through ameliorating nitro-oxidative stress, apoptosis, and inflammation. However, there was no significant difference between melatonin-treated groups. What is known already Recently, the prevalence of testicular cancer (TC), accounting for the most common cancer among young people of reproductive age (15–40 years), has risen internationally. BEP chemotherapy has increased the 5-year survival rate of TC patients at all stages of testicular germ cell tumors to 90–95%. However, BEP creates a high incidence of male infertility and even long-term genotoxic effects, which emerges as a critical health issue. Melatonin is a well-known potent antioxidant with widespread clinical applications that recently has been giving increasing attention to its role in male sub/infertility. Study design, size, duration 60 Adult male Wistar rats were randomly assigned to six groups (n = 10/group). Group 1, 3, and 4 were injected with vehicle, 10 and 20 mg/kg of melatonin, respectively. Other groups received one cycle of bleomycin, etoposide, and cisplatin for a total of 3 weeks with or without melatonin. Melatonin administration started daily one week before BEP initiation continued on days 2, 9, and 16; and one week after the completion of the BEP cycle. Participants/materials, setting, methods Bodyweight, testes weight, Sperm parameters (count, motility, viability, and morphology), testosterone hormone level, testicular histopathology, stereological parameters, testicular level of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), the expression of Bcl–2, Bax, Caspase–3, p53, and TNF-α (Real-time PCR and immunohistochemistry) were evaluated at the end of the study (day 35). Main results and the role of chance Our findings showed that melatonin restores the BEP-induced reduction in the body and testes weight (P<.05). the evaluation of quantitative analysis of the testes stereological procedures, QRT-PCR examination and immunohistochemical (IHC) staining revealed that melatonin reverses the BEP-induced impaired spermatogenesis (P<.05). Furthermore, melatonin rectifies BEP-induced disturbance on sperm count, motility, viability, and morphology. The testosterone level in the BEP-treated group was decreased significantly by comparison with the control group (P<.01). By contrast, co-administration of 10 and 20 mg/kg of melatonin could enhance the serum testosterone level significantly (P<.05). Moreover, melatonin enhanced the antioxidant status of the testis by elevating TAC and ameliorating MDA and NO levels. More notably, QRT-PCR examination indicated that melatonin therapy suppressed BEP-induced apoptosis by modulating apoptosis-associated genes such as Bcl–2, Bax, Caspase–3, p53 in the testis (P<.01). Besides, Co-administration of 10 and 20 mg/kg of melatonin with BEP regimen decreased significantly the population of p53 (54.21 ±6.18% and 51.83±8.45, respectively) and TNF-α positive cells (42.91±9.92% and 33.57±2.97, respectively) by comparison to the BEP group. Also, melatonin with low and high doses could enhance the expression of Bcl–2 protein in spermatogenic cells line (59.19±10.18%, 63.08±5.23, respectively) compared to the BEP-treated group. Limitations, reasons for caution Owing to limited laboratory facilities we were not able to perform further studies to verify the mechanism of melatonin in the specific targets by using transfection technique and transgenic. Wider implications of the findings: These findings can draw attention to the clinical application of melatonin and also suggest that melatonin may be an attractive agent for attenuating chemotherapy-associated male sub/infertility. This indolamine also may shorten the fertility recovery period in patients undergoing chemotherapy with the BEP regimen. Trial registration number N/A

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Significance of Crescentic Glomeruli in Acute Kidney Injury with Rheumatoid Arthritis

Case Reports in Nephrology and Dialysis ◽

10.1159/000500105 ◽

2019 ◽

Vol 9 (1) ◽

pp. 42-48

Author(s):

Ali Ayaash ◽

Dipesh Maan ◽

Anastasios Kapetanos ◽

Mark Bunker ◽

Mary Chester Wasko ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Acute Kidney Injury ◽

Kidney Injury ◽

Renal Outcome ◽

Primary Role ◽

Tubular Necrosis ◽

Immune Mediated ◽

Autoimmune Conditions ◽

Spontaneous Improvement

Crescentic glomerulonephritis (GN) without immune reactants or deposits (referred to as pauci-immune) is typically characterized by the presence of anti-neutrophilic cytoplasmic antibodies (ANCA). While ANCA-negative patients might be expected to have a more benign course, they often have poor renal outcomes, especially without treatment with steroids and immune-modulating therapy. Pauci-immune crescentic GN can also co-exist with other autoimmune conditions, including rheumatoid arthritis (RA). Here, we describe an ANCA-negative patient with RA who developed dialysis-requiring acute kidney injury (AKI) with findings consistent with focal pauci-immune crescentic GN (i.e., no IgG or immune complex on kidney biopsy). Coexistent conditions included Klebsiella sepsis attributed to pneumonia, rhabdomyolysis, leukocytoclastic immune-mediated skin vasculitis, and positive ANA. He had spontaneous improvement in renal function without immunosuppressive therapy. This crescentic GN was not associated with poor renal outcome as AKI resolved with supportive care and treatment of his infection. The AKI was likely multifactorial with co-existing acute tubular necrosis in the setting of Kebsiella sepsis and rhabdomyolysis, and the crescentic GN was felt more likely to be related to the infection rather than having a primary role. This case highlights the importance of viewing crescentic GN in the context of the clinical picture, as it may not always lead to the need of aggressive immune suppression and is not a universally poor prognostic kidney finding. However, these cases do warrant close follow-up as our patient had recurrent RA disease manifestations over the next 2 years that eventually led to his death from severe pulmonary hypertension.

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Cochrane meta-analysis: teicoplanin versus vancomycin for proven or suspected infection

Einstein (São Paulo) ◽

10.1590/s1679-45082011ao2020 ◽

2011 ◽

Vol 9 (3) ◽

pp. 265-282 ◽

Cited By ~ 2

Author(s):

Diogo Diniz Gomes Bugano ◽

Alexandre Biasi Cavalcanti ◽

Anderson Roman Goncalves ◽

Claudia Salvini de Almeida ◽

Eliézer Silva

Keyword(s):

Acute Kidney Injury ◽

Adverse Events ◽

Data Extraction ◽

Meta Analysis ◽

Random Effect ◽

Random Effect Model ◽

Kidney Injury ◽

Serum Levels ◽

Suspected Infection ◽

Red Man Syndrome

ABSTRACT Objective: To compare efficacy and safety of vancomycin versus teicoplanin in patients with proven or suspected infection. Methods: Data Sources: Cochrane Renal Group's Specialized Register, CENTRAL, MEDLINE, EMBASE, nephrology textbooks and review articles. Inclusion criteria: Randomized controlled trials in any language comparing teicoplanin to vancomycin for patients with proven or suspected infection. Data extraction: Two authors independently evaluated methodological quality and extracted data. Study investigators were contacted for unpublished information. A random effect model was used to estimate the pooled risk ratio (RR) with 95% confidence interval (CI). Results: A total of 24 studies (2,610 patients) were included. The drugs had similar rates of clinical cure (RR: 1.03; 95%CI: 0.98-1.08), microbiological cure (RR: 0.98; 95%CI: 0.93-1.03) and mortality (RR: 1.02; 95%CI: 0.79-1.30). Teicoplanin had lower rates of skin rash (RR: 0.57; 95%CI: 0.35-0.92), red man syndrome (RR: 0.21; 95%CI: 0.08-0.59) and total adverse events (RR: 0.73; 95%CI: 0.53-1.00). Teicoplanin reduced the risk of nephrotoxicity (RR: 0.66; 95%CI: 0.48-0.90). This effect was consistent for patients receiving aminoglycosides (RR: 0.51; 95%CI: 0.30-0.88) or having vancomycin doses corrected by serum levels (RR: 0.22; 95%CI: 0.10-0.52). There were no cases of acute kidney injury needing dialysis. Limitations: Studies lacked a standardized definition for nephrotoxicity. Conclusions: Teicoplanin and vancomycin are equally effective; however the incidence of nephrotoxicity and other adverse events was lower with teicoplanin. It may be reasonable to consider teicoplanin for patients at higher risk for acute kidney injury.

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P0517RENAL STEM CELLS (ARPCS) AS A NEPHROPROTECTIVE APPROACH DURING CISPLATIN-INDUCED ACUTE KIDNEY INJURY: A DEFENSE MECHANISM BY EXTRACELLULAR VESICLES CARRYING THE CYP1B1 GENE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa143.p0517 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

ROSSANA FRANZIN ◽

Fabio Sallustio ◽

Claudia Curci ◽

Simona Simone ◽

Angela Picerno ◽

...

Keyword(s):

Gene Expression ◽

Acute Kidney Injury ◽

Extracellular Vesicles ◽

Caspase 3 ◽

Defense Mechanism ◽

Kidney Injury ◽

The Body ◽

Cell Culture Supernatant ◽

Protective Agent ◽

Cyp1b1 Gene

Abstract Background and Aims Cisplatin, is a nonspecific cytotoxic agent that primarily interferes with cellular DNA replication and the cell cycle, nevertheless it lacks tumor selectivity and acts also in normal cells. The most serious adverse reaction of cisplatin is Acute Kidney Injury (AKI), limiting its use and efficacy in chemotherapy. Cisplatin nephrotoxicity is observed in more than 30% of older patients, however the mechanism of nephrotoxicity remains unclear and specific preventive measures are not available. Today, there is an urgent need for specific nephroprotective strategies to be used during cisplatin chemotherapy. Recently, we found that tubular stem/progenitor cells (tARPC) are able to protect the tubular epithelial (RPTEC) from cisplatin induced injury, preserving their proliferation and inhibiting apoptosis. The aim of this study was to identify the molecular mechanisms involved in tARPC-mediated resistance to cisplatin. Method Co-cultures of RPTEC cells and tARPCs were exposed to cisplatin (2.5 µM) for 6 h and then kept in culture for 96 h. Gene expression profile was obtained from tARPCs and RPTECs by Agilent SurePrint G3 Human Gene Expression Microarrays. Genespring and R software were used for the analysis. Gene expression data were validated by Real-time PCR. Extracellular vesicles were isolated from cell culture supernatant by miRCURY Exosome Cell/Urine/CSF Kit (Qiagen) and RNA contained in extracellular vesicles was purified, analyzed in quality by Bioanalyzer (RNA nano) and evaluated by qPCR. The BrdU assay and caspase 3 were used to measure proliferation and apoptosis levels. Immunohistochemical expression of activated caspase-3 was used as a marker of apoptosis in RPTECs. Results By a whole-genome gene expression analysis, we found 107 genes specifically modulated by RPTECs in response to cisplatin and, among these, 30 genes induced by ARPCs following the cisplatin damage. In particular, we found a strong upregulation of the CYP1B1 gene (false discovery rate corrected p value <0.05; fold change=4,1). The qPCR confirmed the increase in CYP1B1 levels in the co-cultures with respect to the respective basal conditions (p <0.05). Interestingly, the CYP1B1 mRNA was also enveloped in Extracellular Vesicles released in the cell co-culture media by tARPC and RPTEC after cisplatin exposition. The CYP1B1 gene encodes a member of the cytochrome P450 superfamily of enzymes and the produced enzyme metabolizes procarcinogens, such as polycyclic aromatic hydrocarbons. CYP1B1 has been shown to be active within tumors and is also capable of metabolizing a structurally diverse range of anticancer drugs. It is responsible for the resistance to docetaxel, cisplatin, tamoxifen and nucleoside analogues. CYP1B1 is involved in the detoxification of the body by various exogenous toxic agents, including cisplatin. We found that CYP1B1 gene was expressed at low levels in RPTECs and in cisplatin-damaged RPTECs. Moreover, 96 h days after 2.5 μM exposure to cisplatin, RPTECs reduced the proliferation and underwent in apoptosis, as showed by caspase 3. However, in co-culture with ARPCs, ARPC cellular and extracellular vesicles CYP1B1 gene expression significantly increased, the apoptotic process was stopped and RPTECs increased their proliferation rate. These data support the hypothesis that ARPCs are sensor of cisplatin damaged-RPTEC and confers cisplatin resistance by transferring CYP1B1 gene in extracellular vesicles. Conclusion This is the first evidence of a cisplatin-induced overexpression of CYP1b1 in renal epithelial cells as a defense mechanism against cisplatin toxicity. This is consistent with our previous data showing that renal progenitors are resistant to cisplatin. The findings may have biological and clinical significance in terms of their implications in cellular communications and potential use of CYP1B1 as biomarkers for AKI induced by cisplatin or as protective agent.

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