Ameliorative Effects of the Aqueous Extract of Allium porrum (Wild Leek) against Cisplatin-Induced Nephrotoxicity in Rabbits

The aim of the present study was to investigate the nephroprotective, hypolipidemic and hypoglycemic effects of Allium porrum (leek) in rabbits with cisplatin nephrotoxicity. Forty adult male New Zealand rabbits were divided randomly into four groups (ten rabbits in each group) as follows: Group I: (negative control) (C) received oral daily dose of distilled water for 15 successive days. Groups II: (Leek) (L) received oral daily dose of aqueous leek extract (500mg/kg/day) for 15 successive days. Group III: (positive control) [cisplatin (CP)] received oral daily dose of distilled water for 15 successive days, and subsequently administered single dose of Cisplatin (3.5mg/kg/day) by intraperitoneal injection from day 10 for five days. Groups IV: (Leek and Cisplatin

Dysregulated MicroRNAs as Biomarkers or Therapeutic Targets in Cisplatin-Induced Nephrotoxicity: A Systematic Review

The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.

Autophagy in Cisplatin Nephrotoxicity during Cancer Therapy

Cisplatin is a widely used chemotherapeutic agent but its clinical use is often limited by nephrotoxicity. Autophagy is a lysosomal degradation pathway that removes protein aggregates and damaged or dysfunctional cellular organelles for maintaining cell homeostasis. Upon cisplatin exposure, autophagy is rapidly activated in renal tubule cells to protect against acute cisplatin nephrotoxicity. Mechanistically, the protective effect is mainly related to the clearance of damaged mitochondria via mitophagy. The role and regulation of autophagy in chronic kidney problems after cisplatin treatment are currently unclear, despite the significance of research in this area. In cancers, autophagy may prevent tumorigenesis, but autophagy may reduce the efficacy of chemotherapy by protecting cancer cells. Future research should focus on developing drugs that enhance the anti-tumor effects of cisplatin while protecting kidneys during cisplatin chemotherapy.

VEGFR3 tyrosine kinase inhibition aggravates cisplatin nephrotoxicity

Expansion of renal lymphatic networks, or lymphangiogenesis (LA) is well-recognized during development, and is now being implicated in kidney diseases. Though LA is associated with multiple pathological conditions, very little is known about its role in acute kidney injury (AKI). The purpose of this study was to evaluate the role of LA in a model of cisplatin-induced nephrotoxicity. LA is predominately regulated by VEGF-C and VEGF-D, ligands that exert their function through their cognate receptor VEGFR3. We demonstrate the use of MAZ51, a selective VEGFR3 inhibitor, which caused significantly worse structural and functional kidney damage in cisplatin nephrotoxicity. Apoptotic cell death and inflammation were also increased in the MAZ51 treated animals compared to vehicle-treated animals following cisplatin administration. Notably, MAZ51 caused significant upregulation of intrarenal phospho-NF-kB, phospho-JNK, and IL-6. Cisplatin nephrotoxicity is associated with vascular congestion due to endothelial dysfunction. Using three-dimensional tissue cytometry, a novel approach to explore lymphatics in the kidney, we detected significant vascular autofluorescence attributed to erythrocytes in cisplatin alone treated animals. Interestingly, no such congestion was detected in MAZ51 treated animals. We found increased renal vascular damage in MAZ51 treated animals, whereby MAZ51 caused a modest decrease in endothelial markers Emcn and vWF, with a modest increase in VEGFR2. Our findings identify a protective role for de novo LA in cisplatin nephrotoxicity and provide a rationale for the development of therapeutic approaches targeting LA. Our studies also suggest off target effects of MAZ51 on the vasculature in the setting of cisplatin nephrotoxicity.

Regression Modeling of the Antioxidant-to-Nephroprotective Relation Shows the Pivotal Role of Oxidative Stress in Cisplatin Nephrotoxicity

The clinical utility of the chemotherapeutic drug cisplatin is significantly limited by its nephrotoxicity, which is characterized by electrolytic disorders, glomerular filtration rate decline, and azotemia. These alterations are consequences of a primary tubulopathy causing injury to proximal and distal epithelial cells, and thus tubular dysfunction. Oxidative stress plays a role in cisplatin nephrotoxicity and cytotoxicity, but its relative contribution to overall toxicity remains unknown. We studied the relation between the degree of oxidative reduction (provided by antioxidant treatment) and the extent of nephrotoxicity amelioration (i.e., nephroprotection) by means of a regression analysis of studies in animal models. Our results indicate that a linear relation exists between these two parameters, and that this relation very nearly crosses the value of maximal nephroprotection at maximal antioxidant effect, suggesting that oxidative stress seems to be a pivotal and mandatory mechanism of cisplatin nephrotoxicity, and, hence, an interesting, rationale-based target for clinical use. Our model also serves to identify antioxidants with enhanced effectiveness by comparing their actual nephroprotective power with that predicted by their antioxidant effect. Among those, this study identified nanoceria, erythropoietin, and maltol as highly effective candidates affording more nephroprotection than expected from their antioxidant effect for prospective clinical development.

Pharmacologically Inhibiting Glycogen Synthase Kinase-3β Ameliorates Renal Inflammation and Nephrotoxicity in an Animal Model of Cisplatin-Induced Acute Kidney Injury

The adverse effect of cisplatin administration causes acute kidney injury (AKI) following renal inflammation and nephrotoxicity, characterized by proximal tubular cell apoptosis and necrosis. Pro-apoptotic and pro-inflammatory roles of glycogen synthase kinase (GSK)-3β have been reported. This study investigated the therapeutic blockade of GSK-3β in cisplatin-induced AKI. A renal cisplatin nephrotoxicity model showed activation of GSK-3β in vivo, particularly in proximal tubular epithelial cells. Pharmacologically inhibiting GSK-3β abolished cisplatin nephrotoxicity, including proximal tubular injury, cell cytotoxicity, and biochemical dysfunction. Additionally, GSK-3β inhibitor treatment ameliorated renal inflammation by reducing immune cell infiltration, cell adhesion molecule expression, and pro-inflammatory cytokine/chemokine production. Cisplatin treatment caused GSK-3β activation in vitro in the human renal proximal tubular epithelial cell line HK-2, whereas either pharmacological administration of GSK-3β inhibitors or genetic transduction of GSK-3β short-hairpin RNA impeded cisplatin-induced cytotoxicity. These results indicate that cisplatin activates GSK-3β followed by GSK-3β-mediated renal inflammation and nephrotoxicity, contributing to AKI.

Protective effect of Phytochemicals against Cisplatin induced Nephrotoxicity

Cisplatin is an inorganic platinum-based oncologic medication and has a broad spectrum of uses in the therapeutic management of number of solid malignant tumour. FDA approved the clinical use of cisplatin in the year 1978. Since then, it has been used alone or in combination with other drugs in chemotherapy. Though, it has highly cured rate for the treatment of cancer, the use of cisplatin is limited due to its major dose limiting side effects such as nephrotoxicity and ototoxicity. The development of cisplatin nephrotoxicity is complex and a number of interrelated factors such as transporter mediated cisplatin accumulation, conversion into nephrotoxins, formation of DNA adducts, mitochondrial dysfunction, nitrosative and oxidative stress, inflammation, signal transducers and apoptotic pathway activation are involved. A number of synthetic drugs are available for the management of cisplatin toxicity but associated with a number of serious side effects such as hypotension, ototoxicity, nausea, vomiting and decreased calcium levels. In addition, various reports show that most of these compounds show unwanted tumour protective activity. Literature review suggested that phytochemicals are reported to have preventive activity in CIRT and it is evident that these compounds showed a pronounced renoprotective activity against CIRT. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically