Colistin is a cationic cyclic lipopeptide antibiotic used against multidrug-resistant Gram-negative bacteria; however, its clinical application is limited by nephrotoxicity. Although oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress are implicated in the primary cytotoxic mechanisms, the secondary inflammatory pathways remain poorly understood. In this study, we aimed to elucidate the mechanisms underlying colistin-induced nephrotoxicity by analyzing the molecular responses of injured renal tubules isolated by laser microdissection (LMD) in a rat model. Six-week-old male Sprague–Dawley rats were subcutaneously administered colistin (0, 15, or 30 mg/kg/day) for 28 days. Increases in serum creatinine and blood urea nitrogen were associated with tubular vacuolation, single-cell necrosis, and regenerative changes in proximal tubules. Immunohistochemistry revealed increased expression of kidney injury molecule-1 (KIM-1) and presence of cleaved caspase-3 in the injured tubules, indicating epithelial regeneration and apoptosis, respectively. LMD-based microarray analysis identified 486 upregulated and 472 downregulated genes in vacuolated/regenerative tubules compared with normal tubules. Pathway analysis indicated activation of immune-related processes, particularly associated with macrophage activation and trafficking, including interleukin-34 (IL-34). In situ hybridization confirmed Il34 mRNA expression in the cytoplasm of the injured tubules, and accumulation of CD68-positive macrophages around KIM-1-positive tubules. Conversely, no significant change was observed in CD163-positive macrophages following colistin treatment, suggesting proinflammatory M1 macrophage predominance. These findings indicate that tubular IL-34 induction and subsequent macrophage recruitment amplify colistin-induced nephrotoxicity at the secondary level, suggesting that proximal tubules function as both primary targets and effectors of inflammation. Targeting the IL-34-related signaling could thus serve as a potential approach to alleviate colistin-induced renal injury.
Matsushita et al. (Thu,) studied this question.