Cisplatin-induced Kidney Research Articles

Melatonin exhibits partial protective effects against gemcitabine- and cisplatin-induced kidney and reproductive injuries in mice.

Cisplatin has the potential to cause kidney and reproductive organ injuries, prompting the search for protective agents against cisplatin-induced toxicity. Melatonin, an antioxidant hormone, has shown promise in mitigating oxidative stress in various organs. However, its protective effects on cisplatin-induced kidney and reproductive injuries have not been extensively investigated. The aim of this study was to explore the potential protective effects of melatonin on cisplatin-induced kidney and reproductive injuries when administered in combination with gemcitabine in mice. Male C57BL/6 mice were subjected to a seven-week treatment with gemcitabine plus cisplatin, with or without melatonin intervention. The testis, epididymis, and kidney were assessed through histological analysis and measurement of blood parameters. Treatment with cisplatin led to a significant reduction in testicular weight, histological abnormalities, and alterations in reproductive hormone levels. Melatonin exhibited a slight protective effect on the testis, with higher doses of melatonin yielding better outcomes. However, melatonin did not reverse the effects of cisplatin on the epididymis. Administration of melatonin before and during treatment with cisplatin plus gemcitabine in mice demonstrated a modest protective effect on testicular injuries, while showing limited effects on epididymal injuries. Serum creatinine levels in the group treated with gemcitabine plus cisplatin treatment and high-dose melatonin approached those of the control group, indicating a protective effect on the kidney. These findings underscore the potential of melatonin as a protective agent against cisplatin-induced kidney and reproductive injuries and emphasize the need for further research to optimize its dosage and evaluate its long-term effects.

Quantitative super-resolution microscopy reveals promoting mitochondrial interconnectivity protects against AKI.

The root of many kidney diseases in humans can be traced to alterations or damage to subcellular organelles. Mitochondrial fragmentation, endoplasmic reticulum (ER) stress, and lysosomal inhibition, among others, ultimately contribute to kidney injury and are the target of therapeutics in development. Although recent technological advancements allow for the understanding of disease states at the cellular level, investigating changes in subcellular organelles from kidney tissue remains challenging. Using structured illumination microscopy, we imaged mitochondria and other organelles from paraffin sections of mouse tissue and human kidney biopsy specimens. The resulting images were 3D rendered to quantify mitochondrial size, content, and morphology. Results were compared with those from transmission electron microscopy and segmentation. Super-resolution imaging reveals kidney tubular epithelial cell mitochondria in rodent and human kidney tissue form large, interconnected networks under basal conditions, which are fragmented with injury. This approach can be expanded to other organelles and cellular structures including autophagosomes, ER, brush border, and cell morphology. We find that, during unilateral ischemia, mitochondrial fragmentation occurs in most tubule cells, and they remain fragmented for >96 hours. Promoting mitochondrial fusion with the fusion promotor M1 preserves mitochondrial morphology and interconnectivity and protects against cisplatin-induced kidney injury. We provide, for the first time, a nonbiased, semiautomated approach for quantification of the 3D morphology of mitochondria in kidney tissue. Maintaining mitochondrial interconnectivity and morphology protects against kidney injury. Super-resolution imaging has the potential to both drive discovery of novel pathobiologic mechanisms in kidney tissue and broaden the diagnoses that can be made on human biopsy specimens.

P0530A NOVEL LNCRNA(LRAN9884) PROMOTES AKI VIA MAINTAINING MINCLE-DEPENDENT M1 MACROPHAGE PHENOTYPE

Abstract Background and Aims Macrophages are key inflammatory cells and play a critical role in renal inflammation in acute kidney injury (AKI). M1 inflammatory macrophage and M2 anti-inflammatory macrophage act reverse role. Phenotype of macrophages is highly flexible and can be changed over time. However, the underlying mechanism of M1 and M2 macrophage phenotype switching during AKI is still largely unclear. In our previous study, we identified a novel lncRNA (LRNA9884) might contribute to inflammation according to modifying macrophages. The present study was designed to uncover the pathogenic role and the underlying mechanism of LRNA9884 in cisplatin-induced AKI. Method Expression level and pattern of LRNA9884 were examined in cisplatin-induced AKI mice. The regulatory mechanisms of LRNA9884 was investigated in cultured bone marrow–derived macrophages (BMDMs) in vitro by silencing or overexpressing of LRNA9884. Flow Cytometer, fluorescence in situ hybridization (FISH) and other multiple molecular biological techniques were applied to figure out the role of LRNA9884 under acute kidney injury. Results LRNA9884 was significantly upregulated in the kidney of cisplatin-induced mice and was associated with the progression of the renal inflammation by using RT-PCR and ISH assay. FISH assay with immunofluorescence co-staining detected that LRNA9884 was largely expressed in the nucleus of macrophage in cisplatin-induced mice kidney compared with the sham group at day 1 after AKI injury. LRNA9884 was remarkedly induced by TNF-α (10ng/ml) in BMDMs as time- and dose- dependent. Western blot and RT-PCR showed that silencing of LRNA9884 effectively inhibited upregulated of macrophage-inducible C-type lectin (Mincle) and iNOS induced by TNF-α. More importantly, we identified that LRNA9884 maintained M1 macrophages phenotype by triggering mincle production at transcriptional level as evidenced by ChIP assay. Conclusion LRNA9884 is a mincle-dependent lncRNA that highly-expressed in macrophages under AKI development. Targeting of LRNA9884 effectively blocked the inflammatory response via promoting the transition M1 macrophage to M2 macrophage phenotype. This study will shed new lights on the understanding of pathological role of novel LRNA9884 in AKI.

Protective Effect of Sika Deer (Cervus nippon) Velvet Antler Extract against Cisplatin-Induced Kidney and Liver Injury in a Prostate Cancer PC-3 Cell Xenograft Model

We previously discovered the antioxidant and antiprostate cancer effects of antler extract (AE), but whether it inhibits cisplatin- (Cis-) induced toxicity has not been investigated. In this study, the effect of AE on Cis-induced side effects in the kidney and liver using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide-based cytotoxicity and cell cycle assays in prostate cancer PC-3 cells in vitro is investigated. Furthermore, we used a xenograft mouse model of the same cells to examine the in vivo effects and mechanisms of action. Cis and Cis + AE treatment attenuated prostate cancer cell growth by inducing apoptosis in vitro. Cis + AE stimulated cleaved caspases 3, 7, and 9 and polyadenosine diphosphate ribose polymerase expression. Cis + AE treatment for 1 week significantly increased the superoxide dismutase and catalase antioxidant activity while thiobarbituric acid reactive substances decreased. The histopathological damage and tumor necrosis factor-α, interleukin- (IL-) 1β and IL-6, cyclooxygenase-2, and inducible nitric oxide synthase expression in the kidney and liver tissue decreased. Therefore, AE likely possesses antiprostate cancer activity and inhibits Cis toxicity.

Assessing the recovery from prerenal and renal acute kidney injury after treatment with single herbal medicine via activity of the biomarkers HMGB1, NGAL and KIM-1 in kidney proximal tubular cells treated by cisplatin with different doses and exposure times

BackgroundAcute kidney injury (AKI) is an initial factor in many kidney disorders. Pre- and intra-renal AKI biomarkers have recently been reported. Recovery from AKI by herbal medicine has rarely been reported. Thus, this study aimed to investigate the dose- and time-dependent effects of herbal medicines to protect against AKI in cisplatin-induced human kidney 2 (HK-2) cells by assessing the activities of high-mobility group box protein 1 (HMGB1), neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1).MethodsProximal tubular HK-2 cell lines were treated with either 400 μM of cisplatin for 6 h or 10 μM of cisplatin for 24 h and then exposed to ten types of single herbal medicines, including Nelumbo nymphaea (NY) at a dose of 100 μg/mL. The AKI biomarkers HMGB1, NGAL and KIM-1 were repeatedly measured by an ELISA assay at 2, 4, and 6 h in the group treated with 400 μM of cisplatin to confirm necrotic cell death and at 6, 24, and 48 h in the group treated with 10 μM of cisplatin to examine apoptotic cell death. Recovery confirm was conducted through in vivo study using ICR mice for 3 day NY or Paeonia suffruticosa intake.ResultsCisplatin treatment at a concentration of 10 μM decreased cell viability. Treatment with 400 μM of cisplatin reduced HMBG1 activity and resulted in lactate dehydrogenase release. In longer exposure durations (up to 48 h), NGAL and KIM-1 exhibited activity from 24 h onward. Additionally, NY treatment resulted in an approximately 50% change in all three biomarkers. The time-dependent profiles of HMGB1, NGAL and KIM-1 activities up to 48 h were notably different; HMGB1 exhibited a 7-fold change at 6 h, and NGAL and KIM-1 exhibited 1.7-fold changes at 24 h, respectively. Consistently, serum and urine NGAL and KIM-1 activities were all reduced in ICR mice.ConclusionsSeveral single herbal medicines, including NY, have a potential as effectors of AKI due to their ability to inhibit the activation of HMGB1, NGAL and KIM-1 in an in vitro AKI-mimicked condition and simple in vivo confirm. Furthermore, an in vivo proof-of-concept study is needed.

The ameliorating effect of Filipendula hexapetala extracts on hepatorenal toxicity of cisplatin

The effects of the methanolic extracts of Filipendula hexapetala Gilib. aerial parts (FHA) and roots (FHR) against cisplatin induced kidney and liver injuries in rats were investigated as well as determination of genotoxicity and antigenotoxicity of the extracts. Treatment with FHA and FHR significantly decreased levels of urea, uric acid, serum transaminases, alkaline phosphatase and γ-glutamyl transferase, and increased the content of total protein. In addition, treatment with the extracts significantly attenuated the cisplatin-induced oxidative stress in kidney and liver tissues by increasing catalase and superoxide dismutase activities and the content of reduced glutathione and decreasing the content of thiobarbituric acid reactive substances (TBARS). The histopathological studies confirmed the protective effects of the extracts against cisplatin-induced kidney and liver injuries. The extracts ameliorated cisplatin-induced genotoxicity. These results suggest that F. hexapetala extracts are effective nephro- and hepatoprotective agents, with potential to reduce oxidative stress and ameliorate cisplatin-induced nephro- and hepatotoxicity.

P0080 Incidence and associated factors of cisplatin-induced chronic kidney disease after chemoradiotherapy for nasopharyngeal carcinoma

Background Cisplatin-based chemoradiotherapy (CRT) is effective and considered a standard of care for treatment of locally advanced nasopharyngeal carcinoma (NPC). Cisplatin-induced nephrotoxicity is problematic in this group of patients because they usually have poor oral intake, dehydration, and malnutrition. Acute kidney injury (AKI) during treatment is a well-known complication that leads to cisplatin discontinuation. However, cisplatin-induced chronic kidney disease (CI-CKD) may not be noticeable during CRT. Methods Patients with non-metastatic NPC who underwent cisplatin-based CRT at Ramathibodi Hospital (Nakhon Pathom, Thailand) between January 2007, and December 2012, were identified through the Ramathibodi Cancer Registry database. Patient characteristics, treatments, baseline, and post-treatment creatinine (⩽6 months after the last dose of chemotherapy) were abstracted. Estimated glomerular filtration rate (eGFR) was calculated by the CKD EPI formula. Patients with AKI were excluded. Primary endpoint was an incidence of CI-CKD, defined by the reduction of eGFR of 20 mg/dl or more from baseline. Findings 245 patients with NPC were identified. 115 eligible patients were included for analysis. All patients had an Eastern Cooperative Oncology Group status of 0–1. Median follow-up was 34.2 months. Overall, CI-CKD was observed in 36 (31%) of 115 patients. Multivariable analysis revealed being female and having a higher total dose of cisplatin during CRT were significantly associated with an increased risk of CI-CKD. Interpretation Approximately a third of patients with NPC suffered from CI-CKD after completion of treatment with cisplatin-based CRT. Total dose of cisplatin during CRT was strongly associated with CI-CKD despite patients being of a young age and with a high baseline eGFR.