Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency

Abstract

Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as a nephroprotector against gentamicin-induced AKI in vitro and in vivo. Porcine renal cells and rats were treated with gentamicin and/or cilastatin. In vivo nephrotoxicity was analyzed by measuring biochemical markers and renal morphology. Different apoptotic, oxidative and inflammatory parameters were studied at cellular and systemic levels. Megalin, mainly responsible for the entry of gentamicin into the cells, was also analyzed. Results show that cilastatin protects cells from gentamicin-induced AKI. Cilastatin decreased creatinine, BUN, kidney injury molecule-1 (KIM-1) and severe morphological changes previously increased by gentamicin in rats. The interference of cilastatin with lipid rafts cycling leads to decreased expression of megalin, and therefore gentamicin uptake and myeloid bodies, resulting in a decrease of apoptotic, oxidative and inflammatory events. Moreover, cilastatin did not prevent bacterial death by gentamicin. Cilastatin reduced gentamicin-induced AKI by preventing key steps in the amplification of the damage, which is associated to the disruption of megalin-gentamicin endocytosis. Therefore, cilastatin might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced AKI in the clinical setting.

Ameliorative impacts of Glycyrrhiza glabra root extract against nephrotoxicity induced by gentamicin in mice

“…It is speculated that this was caused by membrane rupture, releasing gentamicin into the cytoplasm. In turn, this triggers pro‐apoptotic proteins, which damage mitochondria, leading to the release of reactive oxygen species (ROS) and consequent inflammation (Jado et al., 2020).…”

“…Once bound and internalized through endocytosis, gentamicin travels to the endoplasmic reticulum, Golgi apparatus, and lysosomes, causing a build-up of phospholipids, impacting on lipid metabolism, ultimately leading to apoptosis (Martínez-Salgado et al, 2007). (Jado et al, 2020).…”

Effect of Cilastatin on Cisplatin-Induced Nephrotoxicity in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy

“…Therefore, cilastatin prevents absorption of imipenem by increasing urinary excretion and reducing the concentration inside the tubular cells. Previous studies at our hospital and elsewhere showed that cilastatin is effective for reducing the nephrotoxicity of various drugs such as antibiotics [ 47 , 48 ], immunosuppressants [ 49 ], analgesics [ 50 ], and chemotherapeutics without modifying their therapeutic efficacy in target cells. Cilastatin has been shown to protect proximal tubular cells from apoptotic, oxidative, and inflammatory toxic damage induced by cisplatin both in vitro and in vivo by reducing or preventing cisplatin-induced AKI and its worsening [ 15 , 16 , 17 , 18 , 19 ].…”

Tissue Culture Models of AKI: From Tubule Cells to Human Kidney Organoids

“…Gentamicin enters the cells through megalin, a multiligand endocytic receptor located in the apical brush border, and damages the proximal convoluted renal tubule. 15,[118][119][120] Gentamicin forms ternary complexes with iron ions and following oxidation triggers the generation of ROS. 121 Gentamicin accumulates in lysosomes and produces lysosomal phospholipidosis, 122 leading to the impairment of the phosphatidylinositol cascade.…”

“…1). [13][14][15] In podocytes, the plasma membrane monoamine transporter (PMAT) and bisphosphonates mediate disruption of the podocyte cytoskeleton, causing cell death. 16,17 Modeling of kidney injury relies upon both in vivo and in vitro methods.…”