Identification of primary molecule leading to aminoglycoside-induced nephrotoxicity and optimization of molecular-targeted approach for preventing aminoglycoside toxicity

在这项研究中，我们研究了氨基糖苷类抗生素庆大霉素进入肾近端小管细胞系OK和HK-2的分子机制。在表达多配体内吞受体megalin的OK细胞中，庆大霉素是通过依赖内吞作用的途径进入细胞的。另一方面，在只有少量megalin表达的HK-2细胞中，参与庆大霉素摄取的途径不是内吞作用，而是内吞作用依赖途径。此外，研究还表明，HK-2细胞对庆大霉素的非内吞摄取至少部分是通过TRPV阳离子通道转运的。当庆大霉素通过通道依赖的途径进入肾小管细胞时，庆大霉素直接进入细胞质，在那里庆大霉素有效地影响线粒体功能，导致细胞死亡。综上所述，TRPV阳离子通道活性的激活可能会增加氨基糖苷类药物引起的肾毒性的风险。

In this study, we investigated the molecular mechanisms underlying entry of an aminoglycoside antibiotic gentamicin in renal proximal tubular cell lines OK and HK-2. In OK cells expressing a multi-ligand endocytic receptor megalin, gentamicin was taken up into the cells via endocytosis-dependent pathway. On the other hand, in HK-2 cells with little megalin expression, endocytosis-independent pathway, but not endocytosis-dependent pathway, was shown to be involved in gentamicin uptake. In addition, it was suggested that the endocytosis-independent uptake of gentamicin in HK-2 cells is, at least in part, due to transport via TRPV cation channel. When gentamicin is transported via a channel-dependent pathway into renal tubular cells, gentamicin directly enters the cytoplasm, where gentamicin potently affects mitochondrial function leading to cell death. Taken together, it is likely that activation of TRPV cation channel activity increases the risk of aminoglycoside-induced nephrotoxicity.