Drug-induced nephrotoxicity is one of the most frequently observed effects in long-term pharmacotherapy. The effects of nephrotoxicity are commonly discovered later due to a lack of sensitivity in in vivo methods. Therefore, researchers have tried to develop in vitro alternative methods for early identification of toxicity. In this study, LLC-PK1 cells were exposed to gentamicin through MTT and trypan blue assay. Concentrations of 4 (low), 8 (medium) and 12 (high) mM, were used to evaluate differential gene expression. A panel of genes was selected based on gene expression changes. The search for sequences of mRNA encoding proteins previously associated with kidney damage was conducted in the databases of the National Center for Biotechnology Information (USA). RNA was extracted from the cells, and RT-qPCR was performed to evaluate differential expression profiles of the selected genes. Among the 11 analyzed genes, four proved to be differentially up-regulated in cells exposed to gentamicin: HAVcr1, caspase 3, ICAM-1 and EXOC6. According to this study's results, we suggest that these genes play an important role in the mechanism of in vitro nephrotoxicity caused by gentamicin and can be used as early in vitro biomarkers to identify nephrotoxicity when developing safer drugs.

Acute kidney injury (AKI) is a global public health concern, impacting nearly 13.3 million patients and resulting in three million deaths per year. Chronic kidney disease (CKD) has increased by 135% since 1990, representing the pathology with the fastest growth rate worldwide. The annual costs of dialysis and kidney transplants range between US$35,000 and US$100,000 per patient. Despite its great impact, kidney disease has remained mostly asymptomatic for many years. AKI continues to be a major, unmet medical condition for which there are no pharmacological treatments available, while animal models are limited to provide direction for therapeutic translation into humans. Currently, serum creatinine is the standard biomarker to identify nephrotoxicity; however, it is a late stage biomarker. Hence, there is a pressing need to study in vitro biomarkers for the assessment of nephrotoxicity in order to develop new and safer drugs. Understanding of the mechanisms by which molecules produce nephrotoxicity is vital in order to both prevent adversity and treat kidney injury. In this review, we address new technologies and models that may be used to identify earlier biomarkers and pathways involved in nephrotoxicity, such as cell culture, omic approaches, bioinformatics platform, CRISPR/ Cas9 genome-editing, in silico, organoids and 3D bioprinting, considering adverse outcome pathways (AOP).

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