Mechanisms of Melatonin Renal Protection

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI), characterized by a rapid decline in kidney function, is a growing health concern as it is significantly associated with increased morbidity and mortality, as well as reduced quality of life. In particular, vancomycin, an antibiotic commonly used empirically in hospitalized patients, is associated with a 2.45-fold increase in AKI risk. Despite its pronounced nephrotoxicity, the need to cover a broad spectrum of bacteria including potentially resistant strains often limits treatment choices to vancomycin. In a recent retrospective analysis by our research team, patients receiving the sleep medication, melatonin, along with vancomycin had a 63% lower incidence of AKI compared to those receiving vancomycin alone. Melatonin, a hormone that regulates circadian rhythms, is well established for its antioxidant activity. This indoleamine is preferentially taken up by the mitochondria, thereby eliminating free radicals and preserving mitochondrial functions. Melatonin likely also acts as an antioxidant by up-regulating nuclear receptor erythroid 2-related factor 2 (NRF2) target genes involved in the cellular defense system against oxidative stress. Notably, its antioxidant function is speculated to be also mediated through the activation of G-protein coupled melatonin receptors, MT1 (MTNR1A) and MT2 (MTNR1B). Therefore, to address an urgent need to identify novel interventions for management of vancomycin- induced nephrotoxicity, the proposed fellowship will investigate the mechanisms by which melatonin and related pharmacological agents protect against vancomycin toxicity in human kidney cells in vitro. The central hypothesis is that melatonin ameliorates antibiotic-associated kidney injury through coordinated activation of MT receptors and the NRF2-ARE signaling pathway. Aim 1 will investigate the role of melatonin receptor isoforms in mediating the renoprotective effect of melatonin and FDA-approved melatonin receptor agonists against vancomycin kidney toxicity. Immortalized and primary human proximal tubule epithelial cells (HK-2 cells and hPTECs) will be used to evaluate the changes in kidney injury (real-time apoptosis, mitochondrial health, and up-regulation of a proximal tubule injury biomarker), as well as other parameters, including receptor internalization and intracellular drug concentrations. Aim 2 will define the MT-NRF2 signaling gene network responsible for melatonin renoprotection by leveraging a stably transfected HK-2 cell line with disrupted NRF2 activity. RNA sequencing and qPCR will be used to dissect the transcriptomic profiles of genes modulated by the MT-NRF2 network. Consequently, elucidation of the renoprotective mechanisms will provide convincing evidence to re-purpose melatonin for a new clinical indication to prevent vancomycin nephrotoxicity in a cost- effective manner. Upon completion of the proposed studies and training, the Principal Investigator will be well- equipped to ultimately become an independent scientist and faculty member studying drug-induced renal injury at an R1 university.